Method and Computer Program for Controlling the Family-wise
Alpha Rate in Gene Association Studies Involving Multiple
Phenotypes
David B. Allison1 *, Mark Beasley2
1Obesity Research Center, St. Luke's/Roosevelt Hospital,
Columbia University College of Physicians and Surgeons, New York, New York
2Department of Education, St. John's University, Queens, New York
*Correspondence to David B. Allison, Obesity Research Center, St.
Luke's/Roosevelt Hospital, 1090 Amsterdam Avenue, 14th Floor, New York,
NY 10025. E-mail:
DBA8@columbia.edu
Genetic Epidemiology ,
15(1), 87-100 (1998)
Abstract
Multiple significance testing involving multiple phenotypes is not
uncommon in the context of gene association studies but has remained
largely unaddressed. If no adjustment is made for the multiple tests
conducted, the type I error probability will exceed the nominal (per test)
alpha level. Nevertheless, many investigators do not implement such
adjustments. This may, in part, be because most available methods for
adjusting the alpha rate either: 1) do not take the correlation structure
among the variables into account and, therefore, tend to be overly
stringent; or 2) do not allow statements to be made about specific variables
but only about multivariate composites of variables. In this paper we
develop a simulation-based method and computer program that holds the
actual alpha rate to the nominal alpha rate but takes the correlation structure
into account. We show that this method is more powerful than several
common alternative approaches and that this power advantage increases as
the number of variables and their intercorrelations increase. The method
appears robust to marked non-normality and variance heterogeneity even
with unequal numbers of subjects in each group. The fact that gene
association studies with biallelic loci will have (at most) three groups (i.e.,
AA, Aa, aa) implies by the closure principle that, after detection of a
significant result for a specific variable, pairwise comparisons for that
variable can be conducted without further adjustment of the alpha level.
Association Studies