Introduction

Accurate estimation of patient prognosis is important for many reasons. First, prognostic estimates can be used to inform the patient about likely outcomes of her disease. Second, the physician can use estimates of prognosis as a guide for ordering additional tests and selecting appropriate therapies. Third, prognostic assessments are useful in the evaluation of technologies; prognostic estimates derived both with and without using the results of a given test can be compared to measure the incremental prognostic information provided by that test over what is provided by prior information.1 Fourth, a researcher may want to estimate the effect of a single factor (for example, treatment given) on prognosis in an observational study in which many uncontrolled confounding factors are also measured. Here the simultaneous effects of the uncontrolled variables must be controlled (held constant mathematically if using a regression model) so that the effect of the factor of interest can be more purely estimated. An analysis of how variables (especially continuous ones) affect the patient outcomes of interest is necessary to

Tutorials in Biostatistics Volume 1: Statistical Methods in Clinical Studies Edited by R. B. D'Agostino © 2004 John Wiley & Sons, Ltd. ISBN: 0-470-02365-1

ascertain how to control their effects. Fifth, prognostic estimation is useful in designing randomized clinical trials. Both the decision concerning which patients to randomize and the design of the randomization process (for example, stratified randomization using prognostic factors) are aided by the availability of accurate prognostic estimates before randomization.2 Lastly, accurate prognostic models can be used to test for differential therapeutic benefit or to estimate the clinical benefit for an individual patient in a clinical trial, taking into account the fact that low-risk patients must have less absolute benefit (lower change in survival probability).3

To accomplish these objectives, analysts must create prognostic models that accurately reflect the patterns existing in the underlying data and that are valid when applied to comparable data in other settings or institutions. Models may be inaccurate due to violation of assumptions, omission of important predictors, high frequency of missing data and/or improper imputation methods, and especially with small datasets, overfitting. The purpose of this paper is to review methods for examining lack of fit and detection of overfitting of models and to suggest guidelines for maximizing model accuracy. Section 2 covers initial steps such as imputation of missing data, pre-specification of interactions, and choosing the outcome model. Section 3 has an overview of the need for data reduction. In Section 4, we discuss the process of checking whether a hypothesized model fits the data. In Section 5, measures of predictive accuracy are covered. These are not directly related to lack of fit but rather to the ability of the model to discriminate and be well calibrated when applied prospectively. Section 6 covers model validation and demonstrates advantages of resampling techniques. Section 7 provides one modelling strategy that takes into account ideas from earlier sections and lists some miscellaneous concerns. Most of the methods presented here can be used with any regression model. Section 8 briefly describes some statistical software useful in carrying out the strategy summarized in Section 7. Section 9 has a detailed case study using a Cox regression model for time until death in a clinical trial studying prostate cancer.

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