Formal sequential designs have also been proposed for genetic association studies [26]. These can result in substantial cost savings, on average, but have yet to become widely adopted, owing mainly to logistical difficulties. For example, the stopping criteria must be applied to each gene separately, but genotypes are often obtained in bulk in array format, which makes it difficult to apply sequential designs efficiently across many genes. The two-stage designs are a compromise solution using frequentist inference, which also avoid the uncertainty in actual sample size that occurs with sequential inference. Future studies may introduce further design variables. For example, different genotyping technologies may be used in the two stages, with different unit costs, perhaps using DNA pooling [27]. Optimal study designs can be derived for these conditions following current principles.
