Microarrays are an example of powerful high throughput genomics tools that are revolutionizing the measurement of biological systems. In this and other technologies, a number of critical steps are required to convert the raw measures into the results relied upon by biologists and clinicians. These data manipulation have enormous influence on the quality of the ultimate measurements and studies that rely upon them. Our group has previously demonstrated that the use of modern statistical methodology can substantially improve accuracy and precision of gene expression measurements, relative to ad-hoc procedures introduced by designers and manufacturers of the technology. Various companies have now incorporated our methods into their data analysis software (e.g. GeneSpring, GeneTraffic). Microarrays are now being used to measure diverse high genomic endpoints including genotype, chromosomal abnormalities including deletions/insertions, protein binding sites, methylation, and alternative splicing. In each case, the genomic units of measurement are short oligonucleotides referred to as probes. Without appropriate understanding of the bias and variance of these measurements, biological inferences based upon probe analysis will be compromised. In these new technologies, we expect our proposed research to produce statistical methods that facilitate improvements similar to those attained with expression arrays. The need for more research of this kind has grown dramatically in recent years, with the rapid expansion of novel uses of the microarray technology. Our long-term goal is to improve the quality of results obtained using microarray experiments via the use of improved statistical methodology. Toward this goal, the current proposal has the following specific aims: to develop basic analysis tools for the most popular emerging applications, to develop preprocessing methodology to serve the most urgent needs of the user community, and to develop general statistical methodology for population wide hot-spot detection.
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