Grant

Causal analyses, statistical efficiency and phenotypic precision through study design: Genotype based sampling

Funder: Medical Research Council

Dimensions: grant.3560531

Investigators

Affiliations

Organisations

  1. (1) University of Bristol, grid.5337.2

Research Organisations

Countries

United Kingdom

Continents

Europe

Abstract

Using recall frameworks in the design of informative experiments during an era of comprehensive genotypic data collection presents a new and step-changing opportunity. Whilst selection approaches based on physical characteristics can yield groups for targeted follow-up, investigations like this require the availability of study-specific stratum-defining data for all participants and once formed are subject to the limitations of conventional epidemiology. Recall by genotype (RBG) or genotype based sampling is an approach with the potential to maximize the utility of large population-based studies where the collection of genetic data has become routine, but where detailed biological measurement is impractical and random sampling is inefficient. In contrast to other designs, recall (of samples, data or participants) on the basis of genotypic variation has the potential to yield manageable groups for precise measurement in any collection with genetic data. In this programme, RBG will be assessed methodologically and tested in a series of deliverable research projects, each with a specific scientific hypothesis, but also with the aim of exploring the implications of using genetic data in this way. This leader-track programme will produce a methodological toolkit for the undertaking of RBG experiments for the wider research community, deliver a mature programme of research which will place the Unit as a centre of excellence for this approach. Technical Summary A full understanding of the biological underpinnings of health and disease requires appropriate use of genomic data with high quality phenotypic measures. However the exhaustive collection of phenotypic measurements in large studies is impractical and not the most efficient approach to the allocation of finite resources. Therefore the targeted measurement of dense or precise phenotypic characteristics within selected groups is appealing. This programme will comprehensively assess and test the use of genotypes known to be correlated with features of interest, or which require further examination given unexplained correlations with disease, to define strata or subsamples for intense or directed phenotypic data collection. This will allow examination of detailed phenotypic information in financially and pragmatically feasible sample sizes, with analytical power optimized for measurement depth and precision. The motivation for employing genotypic data in this way is the pursuit of causal relationships based on the Mendelian randomization paradigm. This programme will develop and apply Recall By Genotype (RBG): a study design where the recruitment of a sub-set of participants from an existing study, analysis of their biosamples or collection of new data is undertaken on the basis of measured genotypic variation. This work falls naturally into the MRC University of Bristol Integrated Epidemiology Unit (IEU) midway between methodological development and application and intervention, since it aims to (i) develop methods for incorporating prior knowledge of genotype into study design; and (ii) to apply this approach to specific clinical examples. The development of RBG is boundary-pushing as it directly addresses the integration of genetic data into study design, harnesses the theoretical developments around causal inference derived from Mendelian randomization and combines these within study frameworks suitable for the collection of ground-breaking phenotypic data. There are numerous benefits to this approach, however central to this programme is causal inference and the ability of RBG to capture this in relationships observed across strata assigned solely on the basis of genetic variation. This programme will produce an operational toolkit for the application of RBG within MRC/UoB IEU and elsewhere, and will initiate a series of novel studies which will progress into an established programme of genotype-driven study designs.

Resulting publications

Funding information

Funding period: 2013-2018

Funding amount: EUR 1152869

Grant number: MC_UU_12013/3

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Fields of Research