Use of Archived Tissues To Determine Clinical Utility of 使用存档的组织以确定临床实用程序.pptVIP

Find the founder mutations Passenger mutations Occur at rate of synonomous mutations No functional role in oncogenesis and pathogenesis Driver mutations Founder (early) mutations Progression mutations The earliest driver mutations may be of special importance They exist in all sub-clones They permit the tumor to grow to a size in which subsequent mutations occur in a non-rate-limiting manner The subsequent mutations are selected for in the context of the the founder mutations Some tumors may be “addicted” to the early mutations They may represent key molecular targets for treatment Discovering the founder mutations may shed light on the early stages of oncogenesis, intra-tumor heterogeneity and the time course of tumor development, invasion and dissemination “With the appropriate informatic analyses and experimental design, the depth and breadth of sequencing available on the next-generation platforms will provide the tools to reconstruct clonal interrelationships of cancer cell populations, with relevance to identifying and tracking subpopulations of cells responsible for drug resistance, invasion, metastasis, and relapse, as well as annotating the genuinely initiating genetic lesions.” Biotechnology Has Forced Biostatistics to Focus on Prediction This has led to many exciting methodological developments Pn problems in which number of genes is much greater than the number of cases And many erroneous publications Goodness of Fit vs Prediction Accuracy Fit of a model to the same data used to develop it is no evidence of prediction accuracy for independent data “Prediction is difficult; particularly the future.” Dan Quale or Neils Bohr? Prediction on Simulated Null DataSimon et al. J Nat Cancer Inst 95:14, 2003 Generation of Gene Expression Profiles 20 specimens (Pi is the expression profile for specimen i) Log-ratio measurements on 6000 genes Pi ~ MVN(0, I6000) Can we distinguish between the first 10 specimens (Class 1) and the last 10 (Class 2)? Predict