Several investigators have pointed out the possibility of using computer-aided diagnosis (CAD) schemes, as second readers, to help radiologists in the interpretation of images. One of the most important aspects to be considered when the diagnostic imaging systems are analyzed is the evaluation of their diagnostic performance. To perform this task, receiver operating characteristic curves are the method of choice. An important step in nearly all CAD systems is the reduction of false positives, as well as the classification of lesions, using different algorithms, such as neural networks or feature analysis, and several statistical methods. A statistical model more often employed is linear discriminant analysis (LDA). However, LDA implies several limitations in the type of variables that it can analyze. In this work, we have developed a novel approach, based on generalized additive models (GAMs), as an alternative to LDA, which can deal with a broad variety of variables, improving the results produced by using the LDA model. As an application, we have used GAM techniques for reducing the number of false detections in a computerized method to detect clustered microcalcifications, and we have compared this with the results obtained when LDA was applied. Employing LDA, the system achieved a sensitivity of 80.52% at a false-positive rate of 1.90 false detections per image. With the GAM, the sensitivity increased to 83.12% and 1.46 false positives per image.