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YMD
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> Publications by YMD People about Data Analysis > Allison, D.B., and Coffey, C.S. (2002)
Two-Stage Testing in Microarray Analysis:
What is Gained? Journal of Gerontology: Biological Sciences (in press).
Microarray technology for gene expression studies offer powerful new
technology for understanding changes in gene expression as a function of other
observable or manipulable variables. However, microarrays also pose a number of
new challenges. One of the most prominent of these is the difficulty in
establishing a procedure for declaring whether a gene's expression level is
associated with the independent variable that offers reasonable and specifiable
false positive (type 1 error) and false negative (type 2 error) rates. Recently,
Miller et al (2001) offered a two-stage design to address these goals. Miller
et al's approach involves first testing for differences between two groups for
all of k genes in one set of data (stage 1) using an alpha level greater than
the alpha level that would be required by a Bonferroni correction. These k
hypothesis tests will yield some number of genes, m (where m is <k), with
significant effects at this first stage. Then, a second independent set of data
is gathered at stage 2 and only those m genes found to be significant at stage 1
are tested at an alpha level of .05/m.
When introduced, it was stated, but not proven, that this method would
alleviate the problem of false positives (type 1 errors) that would result from
multiple significance testing without correction and false negatives (type 2
errors) that would result from the use of a Bonferroni correction. However, we
(Allison & Coffey, in press) show that this two-stage design often fails to hold
the overall experiment-wise type 1 error rate to some desired alpha level. In
fact, many choices of the per-test alpha level at stage 1 will result in an
experiment-wise type 1 error rate that is overly conservative. Moreover, this
two-stage method can also exacerbate the false negative rate and hence decrease
power relative to a single stage design. Thus, until and unless further
refinements are made, we advocate that investigators not use the two-stage
approach advocated by Miller et al.
Full Article.
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