Sequential Designs for Genetic Epidemiological Linkage or Association Studies A Review of the Literature

Abstract

Objectives. The cost of a genetic linkage or association study is largely determined by the number of individuals to be recruited, phenotyped, and genotyped. The efficiency can be increased by using a sequential procedure that reduces time and cost on average. Two strategies for sequential designs in genetic epidemiological studies can be distinguished: One approach is to increase the sample size sequentially and to conduct multiple significance tests on accumulating data. If significance or futility can be assumed with a certain probability, the study is stopped. Otherwise, it is carried on to the next stage. The second approach is to conduct early linkage analyses on a coarse marker grid, and to increase marker density in later stages. Interim analyses are performed to select interesting genomic areas for follow up. The aim of this article is to give a review on sequential procedures in the context of genetic linkage and association studies. Methods. A systematic literature search was performed in the Medline and the Linkage Bibliography databases. Articles were defined as relevant if a sequential design was proposed or applied in genetic linkage or association studies. Results. The majority of proposed study designs is developed to meet the demands of specific studies and lacks a theoretical foundation. A second group of procedures is based on simulation results and principally restricted to the specific simulated situations. Finally, some theoretically founded procedures have been proposed that are discussed in detail. Conclusions. Although interesting and promising procedures have been suggested, they still lack realizations for practical purposes. In addition, further developments are required to adapt sequential strategies for optimal use in genetic epidemiological studies.

Biostatistical Aspects of Genome‐Wide Association Studies

“…The use of multistage procedures has always been common practice in genetic epidemiological studies (Baeddeker and Ziegler, 2001). Using a GWA as the first step in a multistage procedure is attractive for a number of reasons.…”

Sequential genome‐wide association studies for monitoring adverse events in the clinical evaluation of new drugs

“…See, for example, References [6][7][8][9]. However, these methods have been developed for analysing a ÿxed number of cases and controls, and there seems to have been little application of sequential methods in this area [10].…”

A two-stage design for multiple testing in large-scale association studies

“…Given that the cost of a genetic study is largely determined by the number of individuals recruited and the number of markers genotyped, sequential designs to enhance study efficiency are becoming increasingly popular (e.g., Bo¨ddeker and Ziegler 2001;Saito and Kamatani 2002;van den Oord and Sullivan 2003a, b;Thomas et al 2004;Hirschhorn and Daly 2005). Either samples or marker density or both may be increased sequentially.…”