Filaggrin is a barrier protein in the skin. Two common variants of the filaggrin gene were reported by Palmer et al (Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genetics 2006 Apr;38(4):441-6) to be strongly associated with eczema & these findings have been replicated by others, including us. SPINK5 (serine protease inhibitor Kazal-Type5) gene was discovered in association with Netherton Syndrome, a rare disorder that is ubiquitously associated with severe allergy.

Our collaborators have examined the associations of mutations in SPINK5 and FLG with eczema in a German population. The expected strong association between FLG and eczema was found. There appeared to be no strong evidence of a gene-only association of three mutations of SPINK5 and eczema in this cohort but there was evidence of a possible interaction between SPINK5 and FLG in association with eczema (see Appendix). We now wish to extend these observations by applying the same analyses to the data we have collected as part of our ongoing collaboration on FLG and allergis diseases.

The data are already available in a suitable form for analysis (Kate Northstone). THis proposal is to export these data (questionnaire and clinical assessments of eczema from birth to 13 years) to Dr Irvine & Mclean's German colaborators to carry out identical analytical methods to the attached. This will be more effieicient than analysing the data in-house. THe collaborators are willing to sign a confidentialiuty agreement and they will have access to a limited dataset (only that which is requred for this project under usual ALSPAC rules).

The genotyping costs of this project (FLG & SPINK5) have already been borne by the applicants. There are no additional resoucre issues for this project, which is part of an ongoing programme of analyses in collaboration with ALSPAC core personnel (JH, GDS, KN).

Background:

Debate continues as to the benefit of tonsillectomy. A recent Cochrane review found that there were insufficient trials to fully evaluate the effectiveness of tonsillectomy (1). However, the author of the only studies included in this review stand by their conclusion that tonsillectomy was efficacious in reducing sore throat episodes (1). Furthermore, recent comment from a leading ENT academic asks the pertinent question of the whether the perceived supremacy of this type of review for answering questions related to the use of surgical interventions is justified (2).

Primary question:

Is there a manifest, bias balanced benefit from tonsillectomy versus non-operative management for children with recurrent tonsillitis?

Rationale for using ALSPAC data:

Although there are many studies into the benefit of tonsillectomy, we believe that the ALSPAC database will contain information to add significantly to this debate. Last year there were nearly 30,000 tonsillectomies carried out across England in the 0-14 age group (3). Assuming the national average rate of tonsillectomy applies to the ALSPAC population we expect around 300 tonsillectomies to have been performed on this cohort of children. This study size is comparable with other studies (1).

The incidence of self-reported sore throat is included in the questionnaires, this is the primary outcome that has been previously used to assess benefit of the intervention. However, other outcome measures such as SAT scores and school attendance may be used to demonstrate an association with tonsillectomy. Also, confounders such as socio-economic and smoking status may be examined to balance any potential bias.

Plan of action:

1. We intend to review the ALSPAC database to ascertain the incidence of the exposure variable (tonsillectomy) and the outcome measure (primary being reported sore throat episodes, secondary measures being school attendance/performance).

2. Assess likely bias from confounders between groups.

3. Extract data.

4. Statistical analysis (3. and 4. to be supported by the ALSPAC statistics team, funded by the applicants).

5. Presented locally, regionally and nationally.

6. Publish in the ENT-UK journal (Clinical Otolaryngology).

Several studies in ALSPAC have revealed significant effects of different factors on bone size as assessed by DXA measurements. Interestingly, effects such as social position persist after adjustment for height, suggesting an influence on bone width (1). This observation is important, since influences on bone width imply that bone shape and geometry are being affected, which may have important implications for the risk of sustaining osteoporotic fractures in later life. Therefore, we are keen to explore potential influences on bone geometry in ALSPAC in more detail.

Initial time constraints in the focus clinics limited the acquisition of all three bone scans (Total body and Hip DXA, and PQCT) mainly due to the unfamilarity of the PQCT scanner, therefore we were limited to using only total body DXA and PQCT. However now the operators have become more familiar with the PQCT scanner the length of time required complete this section has been reduced. Therefore at the end of, and breaks in each clinic session there is now time to perform a unilateral hip DXA scan.

Currently total body DXA scans are being performed, and although total body DXA provides important information about bone density in the body it does not provide any information about the shape and strength of the bone. Other groups are currently measuring physical activity within the cohort and it is postulated that bone adapts to the functional requirements placed upon it. The hip is a key area linking the peripheral and axial skeleton together, and due to the geometric orientation of the hip functional stress and strains are very large, and therefore have the potential to show the greatest adaptation to these stresses and strain.

We are currently investigating the effects of physical activity on bone shape and geometry using pQCT as part of a welcome grant. However pQCT is confined to the use of the peripheral skeleton and we can only measure the tibia. Whilst the information gained from this part of the investigation is important due to the direct measurement of shape and geometry, it can not be used to infer information about the hip. Although hip DXA does not directly measure geometry unlike the pQCT, these parameters can be estimated, therefore we are keen to incorporate this scan into the current clinic, especially as there are no extra associated costs incu

We would like to include a unilateral hip DXA, time permitting, in the densitometry element of the data collection clinic. We are proposing to perform all 3 scans in the Age 17 clinic, and have previously collected information on hip geometry at age 13/14. By collecting hip geometry information at age 15/16 we will be better able to investigate the growth and development of bone whilst the young people are going through puberty, and how this may influence osteoporotic fractures later in life.

Hip DXA uniquely estimates the strength and cross sectional area of the hip, this aspect of bone geometry cannot be obtained via the PQCT or the total body DXA. The hip is commonly associated with osteoporotic fractures later in life and th

There have been several studies showing the effects of vitamin supplementation, nutrient deficiency and recent dietary intake on IQ in children [see 1 for a review]. We have recently shown in the ALSPAC cohort that overall dietary patterns in early childhood are associated with both later child behaviour and school performance [2,3]. There appears to be little known about the long-term effects of early diet (with the exception of infant feeding) on later child cognition, as assessed by IQ. The use of dietary patterns aims to overcome the inherent problems of examining individual food and nutrients associations, namely, the inter-correlations between these foods and nutrients. The proposed analysis provides a novel approach to examining the effects of dietary intake on cognitive development.

A preliminary analyses assessing the effects of childhood dietary patterns on IQ has already performed in order to feed into a grant proposal to be submitted to NIH in Feb 08 by Tomas Paus (Nottingham), a primary aim of which is to evaluate the role of nutrition during the first five years of life on brain structure in adolescence.

At his request, I examined the associations between dietary patterns in early childhood (at ages 3, 4, 7 and 8 years [4,5]) and overall IQ assessed at 8 years of age. Initial results suggest that there may be an effect of overall dietary patterns in childhood and IQ. In particular a 1 SD increase in the 'processed' component score at each age (3, 4, 7 and 8) was associated with a decrease of between 2 and 4 points on the WISC IQ scale, while a 1 SD increase in 'health conscious' component score at each age resulted in a 2 point increase. After adjustment for a limited number of confouding or mediating factors the effect sizes were attenuated, though strong relationships remained the 3-year data; as such further analyses is required to take into account additional factors which may be important after a thorough review of the literature. This will determine whether the observed effects are real or due to residual confounding.

Proposed further anlaysis will include:

1. Examining the verbal and performance components of the WISC;

2. Examining the results of the subtests of the WISC;

3. Further adjustment for other factors, including maternal diet, aspects of which have been shown to be associated with IQ in this sample [6];

4. Using cut-offs for IQ in order to determine the risk of poor performance.

Although this work is unfunded it will be of particular use to the NIH grant and is a natural follow-on to the work constituting my PhD. It will also feed into other funding opportunities to investigate the effects of diet on other cognitive and neuro-developmental outcomes.

No outline received

No outline received

No outline received