A substantial number of studies have reported the development of gene expression-based prognostic signatures for lung cancer. The ultimate aim of such studies should be the development of well-validated clinically useful prognostic signatures that improve therapeutic decision making beyond current practice standards. We critically reviewed published studies reporting the development of gene expression-based prognostic signatures for non-small cell lung cancer to assess the progress made toward this objective. Studies published between January 1, 2002, and February 28, 2009, were identified through a PubMed search. Following hand-screening of abstracts of the identified articles, 16 were selected as relevant. Those publications were evaluated in detail for appropriateness of the study design, statistical validation of the prognostic signature on independent datasets, presentation of results in an unbiased manner, and demonstration of medical utility for the new signature beyond that obtained using existing treatment guidelines. Based on this review, we found little evidence that any of the reported gene expression signatures are ready for clinical application. We also found serious problems in the design and analysis of many of the studies. We suggest a set of guidelines to aid the design, analysis, and evaluation of prognostic signature studies. These guidelines emphasize the importance of focused study planning to address specific medically important questions and the use of unbiased analysis methods to evaluate whether the resulting signatures provide evidence of medical utility beyond standard of care-based prognostic factors.

Developments in whole genome biotechnology have stimulated statistical focus on prediction methods. We review here methodology for classifying patients into survival risk groups and for using cross-validation to evaluate such classifications. Measures of discrimination for survival risk models include separation of survival curves, time-dependent ROC curves and Harrell's concordance index. For high-dimensional data applications, however, computing these measures as re-substitution statistics on the same data used for model development results in highly biased estimates. Most developments in methodology for survival risk modeling with high-dimensional data have utilized separate test data sets for model evaluation. Cross-validation has sometimes been used for optimization of tuning parameters. In many applications, however, the data available are too limited for effective division into training and test sets and consequently authors have often either reported re-substitution statistics or analyzed their data using binary classification methods in order to utilize familiar cross-validation. In this article we have tried to indicate how to utilize cross-validation for the evaluation of survival risk models; specifically how to compute cross-validated estimates of survival distributions for predicted risk groups and how to compute cross-validated time-dependent ROC curves. We have also discussed evaluation of the statistical significance of a survival risk model and evaluation of whether high-dimensional genomic data adds predictive accuracy to a model based on standard covariates alone.

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Basket clinical trials are a new category of early clinical trials in which a treatment is evaluated in a population of patients with tumors of various histologic types and primary sites selected for containing specific genomic abnormalities. The objective of such studies is generally to discover histologic types in which the treatment is active. Basket trials are early discovery trials whose results should be confirmed in expanded histology specific cohorts. In this report, we develop a design for planning, monitoring, and analyzing basket trials. A website for using the new design is available at https://brbnci.shinyapps.io/BasketTrials/ and the software is available at GitHub in the "Basket Trials" repository of account brbnci.

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