Amy V Kapp | PubMed Health

PubMed2006

Discovery and validation of breast cancer subtypes.

BACKGROUND: Previous studies demonstrated breast cancer tumor tissue samples could be classified into different subtypes based upon DNA microarray profiles. The most recent study presented evidence for the existence of five different subtypes: normal breast-like, basal, luminal A, luminal B, and ERBB2+. RESULTS: Based upon the analysis of 599 microarrays (five separate cDNA microarray datasets) using a novel approach, we present evidence in support of the most consistently identifiable subtypes of breast cancer tumor tissue microarrays being: ESR1+/ERBB2-, ESR1-/ERBB2-, and ERBB2+ (collectively called the ESR1/ERBB2 subtypes). We validate all three subtypes statistically and show the subtype to which a sample belongs is a significant predictor of overall survival and distant-metastasis free probability. CONCLUSION: As a consequence of the statistical validation procedure we have a set of centroids which can be applied to any microarray (indexed by UniGene Cluster ID) to classify it to one of the ESR1/ERBB2 subtypes. Moreover, the method used to define the ESR1/ERBB2 subtypes is not specific to the disease. The method can be used to identify subtypes in any disease for which there are at least two independent microarray datasets of disease samples.

Algorithms↗

PubMed2006

Are clusters found in one dataset present in another dataset?

In many microarray studies, a cluster defined on one dataset is sought in an independent dataset. If the cluster is found in the new dataset, the cluster is said to be "reproducible" and may be biologically significant. Classifying a new datum to a previously defined cluster can be seen as predicting which of the previously defined clusters is most similar to the new datum. If the new data classified to a cluster are similar, molecularly or clinically, to the data already present in the cluster, then the cluster is reproducible and the corresponding prediction accuracy is high. Here, we take advantage of the connection between reproducibility and prediction accuracy to develop a validation procedure for clusters found in datasets independent of the one in which they were characterized. We define a cluster quality measure called the "in-group proportion" (IGP) and introduce a general procedure for individually validating clusters. Using simulations and real breast cancer datasets, the IGP is compared to four other popular cluster quality measures (homogeneity score, separation score, silhouette width, and weighted average discrepant pairs score). Moreover, simulations and the real breast cancer datasets are used to compare the four versions of the validation procedure which all use the IGP, but differ in the way in which the null distributions are generated. We find that the IGP is the best measure of prediction accuracy, and one version of the validation procedure is the more widely applicable than the other three. An implementation of this algorithm is in a package called "clusterRepro" available through The Comprehensive R Archive Network (http://cran.r-project.org).

Breast Neoplasms↗