Preprocessing and Analysis Tools for Contemporary Microarray Applications

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DESCRIPTION (provided by applicant): After more than a decade of improvements to experimental and data analysis techniques, microarray technology is poised to become instrumental in the era of personalized genomics. In fact, Affymetrix, a leading manufacturer, recently achieved the first FDA clearance of high-throughput gene profiling reagents. Microarrays were also crucial in the successful development of an FDA approved breast cancer recurrence assay - making it possible to identify patients at risk of distant recurrence following surgery. Moreover, approximately one half of all Pub Med publications citing microarrays were published during the last two years. We therefore expect laboratories in academia and industry to continue relying on these technologies for several years as newer genomic technologies mature, and that manufacturers will continue to develop new products at a rapid pace. All microarray data analyses begin by converting raw measures into the data and summary statistics relied upon by biologists and clinicians. This first step, referred to as preprocessing, has an enormous influence on the quality of the ultimate measurements and results from studies that rely upon them. Our group has previously demonstrated that statistical methodology can provide great improvements over ad hoc data analysis algorithms offered as defaults by array manufacturers. Our highly cited statistical methodology and our widely used software implementations demonstrate the success of our work. While gene expression has been the most popular microarray application, recently, the technology has been used to measure diverse genomic endpoints including genotype, copy number variants, transcription factor binding sites, and several epigenetic marks, including DNA methylation. During the first funding period, our group was dedicated to understanding the bias and systematic errors which can obscure results, thwart discovery, and contribute to findings that are not reproducible. We have amassed expertise and developed successful data analysis tools to effectively preprocess raw data, making the technology prime for translational research and clinical applications. However, this transition from basic to clinical research will generate new statistical challenges and our methodology, which has partly facilitated the success of microarrays, will play an important role in the promising next period of research driven by microarray technology. Our goal is to develop the next generation of preprocessing and analysis tools with an emphasis on translational applications. Toward this goal, the current proposal has the following specific aims: developing single array preprocessing methodology with emphasis on batch effect removal, developing microarray analysis tools for three urgent needs, and developing generalized bump hunting methodology for detecting differentially methylated regions.