A) Relationship between glycemic index, dietary protein and myopia.

The Cordain theory [3] proposes that myopia occurs as a result of environmental conditions associated with modern civilisation, which came about after the Palaeolithic era. The prevalence of myopia is very low in hunter-gatherer populations compared to more "advanced" populations (less than 2% vs. greater than 20%) [1]. In Eskimos, increasing acculturation during the 1960's led to a marked increase in myopia prevalence [2]. The typical Palaeolithic diet is characterised as being high in protein, low in fat and low in carbohydrates, particularly low glycaemic index carbohydrates: which are slowly absorbed in the blood stream and produce a gradual and minimal rise in plasma glucose and insulin levels when compared to higher glycaemic foods . As well as being implicated in metabolic syndrome, the modern - lower protein/higher glycaemic index - diet has also been suggested as a potential risk factor for myopia [3].

Dietary protein has also been considered as a possible risk factor for myopia, because protein generally results in lower rises in both plasma glucose and insulin when compared to carbohydrate.

In a number of studies, Gardiner [4,5], indicated that myopic individuals consumed significantly lower amounts of animal protein than non-myopes. Further, in an intervention study (albeit a non-rigorous one) he was able to show that increasing the level of animal protein in the diets of myopic children slowed progression of their myopia when compared to a control group receiving no dietary modification [6].

B) Exploratory analysis: Dietary copper

Normal copper metabolism is essential to ocular tissue health and is associated with myopic refractive error development in some studies [7,8]. A recent study found that mutations in the SCO2 gene were associated with autosomal-dominant high-grade myopia. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Mutations of SCO2 were associated with a destabilisation of protein structures which in turn may result in modulation of oxidative toxicity-particularly in the retina, leading to retinal neuronal thinning. In addition, mutations can affect copper metabolism, which may result in an imbalance of copper enzymatic support activity and oxidative levels within eye tissues [9]. Proper copper metabolism is essential for cell differentiation, development, and maintenance. One study demonstrated the protective effect of copper supplements in individuals with myopia, restoration by capsule injection of copper compounds resulted in increased scleral copper concentration and improved scleral tissue elasticity with cessation of myopic refractive error development [10].

C) Exploratory analysis: Breastfeeding

Observational studies have suggested that breast-feeding benefits the visual development of infants, which has been attributed to the presence of DHA in breast milk but not most formula milks.

In a cross-sectional study of 797 children (ages 10-12 years) in Singapore, the prevalence of myopia was significantly lower in children who had been breastfed than in those who had not (62% vs. 69.1%; p=0.04). The duration of breastfeeding (three months or less versus more than three months) was not associated with myopia risk. However, since the incidence of myopia in children in Singapore is among the highest in the world, it is not clear whether these findings can be generalised to other populations [11].

Analyses of data from three large British birth cohorts showed that there were no differences in visual outcome in childhood or adolescence among those initially breastfed for greater than 1 mo compared with those formula fed. Rates of breastfeeding fell across successive cohorts considerably, but there was no evidence of a subsequent increase in adverse visual outcome in childhood, although, there was a small increase in adverse visual outcome in adolescence from 1946 to 1970. However, the latter did not take into consideration important confounding factors, especially the age at which vision was assessed. (12)

Overall Aim:

To calculate prevalence estimates of a range of self-reported key sexual health indicators and behavioural patterns as assessed in the ALSPAC cohort between the ages of 17 and 22 years of age in order to better understand the sexual health needs of young people in the Bristol area.

AIM:

This aim of this research proposal is to understand the impact that children's early physical and communication environments have on their developing speech and language skills. The findings will be of use to parents, health visitors, health promotion and public health, early years practitioners and educationalists with regard to which environments and behaviours are most helpful in promoting early speech and language development and which can have a deleterious effect. This is particularly important given recent changes in society which mean that children are being brought up in homes where there are numerous devices which can be used to occupy them rather than engage them in conversation. Moreover, other lifestyle factors could also be having an impact but to date have been subject to minimal investigation (e.g. central heating, forward facing buggies, eating together). Whilst there is much evidence on the importance of parent child interaction on the development of speech and language in young children, there has not been the opportunity to date to investigate how this interacts with these other factors relating to the physical environment.

The findings of this study will also be of interest to the government. A recent DfE report based on data from the original ALSPAC sample (Roulstone, Law, Rush, Clegg, Peters, 2011, DFE RR134) found that vocabulary scores at age 2 years old were associated with baseline scores on entry to primary school, which are themselves related to academic outcomes later on. Low academic outcomes and persistent speech and language impairment are both associated with poor social and economic outcomes and a greater cost to the nation. This study will aim to identify factors early on in the child's development, including data collected in the child's home, which could impact on vocabulary at age 2 and language skills and academic skills beyond.

In the course of collecting data on variables which impact on early speech and language development, normative data will be collected using tools which have been developed in the US and for which UK norms are not currently available. These data will be of help to health visitors and early years practitioners in the future as they will assist in the process of early identification of children at risk of speech and language impairment. Currently, children are not typically identified until age 2 at the earliest.

Lipids in general and fatty acids in particular have been implicated in brain development (Simopoulos 2011, Molecular Neurobiology), cognitive ability (Swanson 2012, Advances in Nutrition), and dementia (Reitz 2011, Nature Reviews Neurology). Specific fatty acids, such as DHA, are believed to have a direct effect on cell integrity, development, maintenance, and function in the brain (Bazan 2011, Annual Review of Nutrition). These essential polyunsaturated fatty acids can only be obtained through diet with high levels found in cold water fatty fish, seed oils and green-leafed plants.

Spelling and reading are markers of learning ability and cognitive function (Taylor 2013, Psychological Bulletin). As both diet and learning ability are strongly influenced by socioeconomic level we will use a Mendelian randomisation approach to estimate the causal effects of lipid metabolites and fatty acids on brain function, in children aged seven, as this is measured through spelling and reading tests. For this we will use the identified polymorphisms affecting the metabolites of interest as reported in Ketunnen et al 2012 Nat Genet.

Depending on the results of this effort we will try to obtain funding for a more detailed characterisation of fatty acids in order to gain a better understanding of the mechanisms involved

Using linked routine and bespoke data to better understand inequity in the use of health care services among children.

We will perform a MR study to estimate the effect of age at menarche on parameters of lung function indicative of both restriction (FVC) and obstruction (FEV1/FVC). For this we would like to use ALSPAC lung function data from 16-year old women.

The aim of this study is to identify differential methylation in cord blood that is associated with AMH levels in female and male adolescents (separately) 15 years of age.

Genome-wide association analysis of 2D:4D finger ratio

Rationale:

Ageing, Social science and allostatic load

Many physiological systems are proposed as the mediators that allow social processes to "get under the skin". Allostatic load is conceptualised as the 'wear and tear' associated with the response to chronic or repeated stress (Mcewen and Stellar 1993). The concept has been adopted in many analyses of the association of the social environment with health as it represents the impact on a multiple physiological systems including 'primary' stress pathways and secondary 'intermediate' pathways (Seeman et al., 2001). A number of studies within CLOSER and others that have detailed measures of the social environment have used the concept of allostatic load to examine social, psychological and other exposures (Babosa-Solis et al., 2015, Read & Grundy, 2015; Rod et al., 2015; Robertson et al., 2015). Allostatic load is generally measured through a composite index of indicators that reflect this multi-system approach and include neuroendocrine, metabolic, immune and cardiovascular markers. However operationalisation of allostatic load varies across surveys as it is limited to the availability of biomarkers within studies. Consequently, it is difficult to compare analyses across cohorts. While there are a few studies in younger age groups (Brody et al., 2014), studies that have examined allostatic load are generally conducted in older age groups (Seeman et al., 2010; Gruenwald et al., 2012; Read and Grundy, 2014). It is unclear that the allostatic load construct remains stable by age or by other factors such as medication status (Booth et al., 2014). A number of studies have suggested that allostatic load varies by social position (Seeman et al., 2010; Gruenwald et al., 2012). Again a majority of these studies are conducted in older age groups and, while one suggests that social differences in allostatic load are apparent in those aged under 75 y only (Robertson et al., 2014), further work is required to understand when in the lifespan the association of allostatic load with measures of social position emerges.

Plan of analyses

1)We will catalogue the biomarkers in the component studies within CLOSER and other studies such as Whitehall II, Twenty-07 and ELSA. In doing this we will highlight valuable analytes for social-biological research, and provide guidance on the key issues that need to be considered in their analysis.

2) We would scope the literature to examine which biological markers are typically included in the construction of Allostatic load. Examine which of the identified markers have been collected across the CLOSER studies with a focus on categorising them as components of primary or intermediate and markers. We will then examine how the inclusion/exclusion of typical plus additional markers might affect our understanding of the construct and its social patterning.

Finally we propose three substantive research questions:

1)to operationalise 'allostatic load' across the cohorts with varying inclusion criteria and by medication status.

2)to capitalise on the on-going work package in CLOSER, which has harmonised measures of social position across the CLOSER studies and examine how social position is related to 'Allostatic load'.

3)to capitalise on the wide age range available in with CLOSER studies to examine how allostatic load evolves across the age span.