A distribution-free smoothed combination method of biomarkers to improve diagnostic accuracy in multi-category classification

Results from multiple diagnostic tests are usually combined to improve the overall diagnostic accuracy. For binary classification, maximization of the empirical estimate of the area under the receiver operating characteristic (ROC) curve is widely adopted to produce the optimal linear combination of multiple biomarkers. In the presence of large number of biomarkers, this method proves to be computationally expensive and difficult to implement since it involves maximization of a discontinuous, non-smooth function for which gradient-based methods cannot be used directly. Complexity of this problem increases when the classification problem becomes multi-category. In this article, we develop a linear combination method that maximizes a smooth approximation of the empirical Hypervolume Under Manifolds (HUM) for multi-category outcome. We approximate HUM by replacing the indicator function with the sigmoid function or normal cumulative distribution function (CDF). With the above smooth approximations, efficient gradient-based algorithms can be employed to obtain better solution with less computing time. We show that under some regularity conditions, the proposed method yields consistent estimates of the coefficient parameters. We also derive the asymptotic normality of the coefficient estimates. We conduct extensive simulations to examine our methods. Under different simulation scenarios, the proposed methods are compared with other existing methods and are shown to outperform them in terms of diagnostic accuracy. The proposed method is illustrated using two real medical data sets.