(No outline received).

We propose a pilot analysis using the placental data already collected from the Chidlren in Focus subset (CIF, N=1050), and BMI, waist & fat & lean mass (DXA) at age 9. These pilot analyses will provide strong support for our (generally well received) October submission, and we are optimistic about receiving funding based on our July resubmission. Jon Heron and Jeremy Miles will work together on data analysis, which will be incorporated into the July grant that will include Dr Lawlor, Dr Davey-Smoth and potentially Dr David Barker in the research team.

Previously submitted and approved protocol (our ref B355)

We propose to develop an R01 application utilizing placental data to be submitted as a supplement to the NIH funded R01 "Maternal overnutrition and offspring fat mass, metabolic and vascular function" (Principal Investigator: Dr. Debbie Lawlor, University of Bristol). We outline below the specific aims for such a supplement and provide a model illustrating the integration of these aims with the aims of the currently funded study. While Dr. Lawlor's grant aims refer to "offspring" generally, we have explicitly separated out the neonatal (birth outcomes) within our aims given the focus on the placenta.

SPECIFIC AIMS

Specific Aim 1: To investigate the influence of maternal BMI, weight gain, and diet during pregnancy on placental anthropometric measures. Specifically, we will assess and study the following placental parameters: placental weight, thickness, diameters; umbilical cord length; shape; symmetry measures; chorionic vascular branching pattern). The following null hypotheses will be tested:

1A. Maternal BMI does not explain variation in placental size and shape.

1B. Maternal weight gain does not explain variation in placental size and shape.

1C. Maternal diet does not explain variation in placental size and shape.

Specific Aim 2: To determine whether and how placental size and shape influences birth size. The following null hypotheses will be tested:

2A. Placental size and shape are not associated with birth size (e.g. weight, birth weight ratio, length, ponderal index).

2B. Associations between maternal factors and birth size are mediated by variation in placental size and shape.

Specific Aim 3: To determine whether and how placental size and shape influence offspring growth. Offspring growth was measured at multiple time points beginning at age 1 year up to 15 years of age and includes measures of adiposity (DXA assessed fat mass and fat distribution), vascular function (blood pressure, pulse pressure and endothelial function), and metabolic function (fasting glucose, insulin and lipids). The following null hypotheses will be tested:

3A. Placental size and shape are not associated with offspring childhood adiposity.

3B. Placental size and shape are not associated with offspring childhood vascular function.

3C. Placental size and shape are not associated with offspring childhood metabolic function.

3D. Associations between placental size and shape with offspring outcomes are mediated by effects of the placenta on birth size.

Specific Aim 4: To investigate the role of genetic variation on placental size and shape. DNA was extracted from mothers and offspring in the parent study. The following null hypotheses will be tested:

4A. Genetic variation does not explain variation in placental size and shape.

4B. Interactions between genes and the selected maternal factors (BMI, weight gain, diet) do not explain additional variations in placental size or shape.

Specific Aim 5: To develop and validate a placental index to identify offspring at risk for adverse outcomes with regard to adiposity, vascular function, and metabolic function.

(No outline received).

(No outline received).

Social networks are pervasive. Diverse examples range from friendship groups, neighbourhoods, and the decisions of companies over whom they conduct business with, to more formal networks such as workplaces, political groupings, local voluntary organisations, and international trade organisations. Analysing the formation and evolution of networks is complex and important.

* It is complex because there are two inter-related processes taking place. On one hand, the value any one individual or company gets from belonging to the network, their commitment to it, and the ethos and effectiveness of the network depend crucially on other members of the network. But, at the same time, these factors also influence how the membership changes over time. This complex relationship and feedback provides a rich diversity of potential outcomes and dynamics, not all of which are economically or socially beneficial.

* It is important because networks have important effects on educational outcomes, on employment levels, on social unrest, on how industries grow and decline, etc., and ultimately, through these effects, on the strength of the economy and society. Social networks have been widely studied in a sociological context, but it is only in recent years that the study of such networks has started to affect the way that we think of economic behaviour and the dynamic processes in society and economies. Both theoretical and empirical work in this area is difficult but recent developments in theory and newly available datasets make this possible. This is a new and exciting research agenda, which can provide insights into the importance of collective behaviour and collective norms for economic outcomes, and therefore on the growth of the economy. CMPO has already contributed to this agenda through its work in two distinct areas - corporate culture and neighbourhoods - and, building on this work, we are in a position to make a major contribution to this new field. It is clear from our work and our reading of the other research in this area that this emerging field of study could be pushed forward by a two pronged approach that undertakes (a) theoretical analysis that recognises that the existing

apparently diverse research is really one big issue, and (b) empirical analysis of the development, dynamics and consequences of critical social networks.

Our aim is to undertake a major study with two core, linked, components:

* Theoretical analysis of economic and social networks and communities, and of how different networks interact. The objective is to provide a global analysis that can be used to give deeper insight into specific types of networks. This will build on existing work that is currently based on three distinct but interrelated themes: (i) individual actions based on complementarities, (ii) group formation to achieve group objectives, and (iii) research that focuses on linkages between members.

* A series of econometric studies on large datasets and case studies to test the theories in specific contexts. The topics include (i) the long run implications of patent commons (open-sourced communities where firms share patents), (ii) the transition at retirement from work-based networks to social-based networks, (iii) how workplace networks affect career concerns and career paths, (iv) what is the impact of neighbourhood and peer groups in school on educational outcomes, (v) what is the impact of networks and neighbourhood on productivity and employment, (vi) when and with whom do lasting friendships form among teenagers and how these friendship networks influence educational attainment and criminal or anti-social behaviour.These projects will build on our experience of developing theory alongside empirical analysis, and exploit the skills and the large datasets we have built up over the past 7 years.

We previously received DNA samples from 110 ALSPAC family trios to determine the frequency of germline minisatellite mutations. These were screened for mutations in the CEB1 minisatellite locus and genotypes obtained from 60 families. Following modification of the genotyping method the family trios were re-screened, and genotypes were obtained from 52 families. In a significant number of cases (n=50), no amplification from at least 1 family member prevented us from obtaining a genotype. We belive that this was due to an insufficient amount of DNA. We now wish to assemble a set of genotypes from 200 ALSPAC families. Although DNA from blood samples would be preferable, DNA from LCL might suffice as long as we can establish that a "germline" mutation is not in fact a somatic mutation caused by the establishment of the cell line. We are thus requesting DNA from 148 families, which could include material from the 50 families that originally failed to amplify. In addition, we would like to test samples derived from LCL made from 20 of the 52 genotyped families, so that we can check that the genotypes are the same. In all therefore, we are requesting DNA from 168 family trios, either from LCL or native DNA.

(No outline received).

(No outline received).

It is clear that early life events influence subsequent risk of cardiovascular disease, but the mechanisms involved remain obscure. This proposal will investigate the impact of low birth weight and postnatal growth patterns on the microvasculature of the retina in a birth cohort of children followed over the first 12 years of life. Measurements of retinal microvascular abnormalities will be made using digitally acquired retinal images analysed by an extensively validated semi-automated analysis system. The results of this study will provide novel insights into possible mechanisms linking early life events with future risk of hypertension, cardiovascular disease and diabetes and may contribute to development of appropriate early treatment and intervention