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GENETICS
Analysis of gene expression in pathophysiological states: Balancing false discovery and false negative rates

Andrew W. Norris ^*,  , and C. Ronald Kahn ^*, 

^*Joslin Diabetes Center, Children's Hospital, and Harvard Medical School, Boston, MA 02215

Contributed by C. Ronald Kahn, November 28, 2005

Nucleotide-microarray technology, which allows the simultaneous measurement of the expression of tens of thousands of genes, has become an important tool in the study of disease. In disorders such as malignancy, gene expression often undergoes broad changes of sizable magnitude, whereas in many common multifactorial diseases, such as diabetes, obesity, and atherosclerosis, the changes in gene expression are modest. In the latter circumstance, it is therefore challenging to distinguish the truly changing from nonchanging genes, especially because statistical significance must be considered in the context of multiple hypothesis testing. Here, we present a balanced probability analysis (BPA), which provides the biologist with an approach to interpret results in the context of the total number of genes truly differentially expressed and false discovery and false negative rates for the list of genes reaching any significance threshold. In situations where the changes are of modest magnitude, sole consideration of the false discovery rate can result in poor power to detect genes truly differentially expressed. Concomitant analysis of the rate of truly differentially expressed genes not identified, i.e., the false negative rate, allows balancing of the two error rates and a more thorough insight into the data. To this end, we have developed a unique, model-based procedure for the estimation of false negative rates, which allows application of BPA to real data in which changes are modest.

metabolic disease | microarray analysis | multiple hypothesis testing | statistics

Abbreviations: BPA, balanced probability analysis; FDR, false discovery rate; FNR, false negative rate; TTP, number of total true positives.

Present address: Department of Pediatrics, Roy and Lucille Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109. E-mail: andrew-norris{at}uiowa.edu.

To whom correspondence should be addressed at: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: c.ronald.kahn{at}joslin.harvard.edu.

© 2006 by The National Academy of Sciences of the USA

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