To avoid the pitfalls of population-based association studies, Spielman and Ewens (1996) developed a family-based association test—the transmission disequilibrium test (TDT). The primary advantage of the TDT is that it avoids the necessity of including a matched control sample. As originally proposed, the TDT analyzes a nuclear trio consisting of an affected person and his or her parents (see figure 3B). For these three people, researchers then determine the genotype of a marker in or near the candidate gene. If each parent carries two different alleles of the marker gene, then one allele from each parent will be transmitted to the affected offspring and one allele will not be transmitted. Those alleles that have been transmitted from the parents to the affected offspring are considered the “affected” sample, and the remaining alleles are used as “control” sample. Using the information on the transmission of various alleles from many families, investigators can conduct statistical analyses to determine if a particular allele of the marker being tested is associated with disease development. Through the use of such a “within-family” design, the control
