Statistical shape model for manifold regularization: Gleason grading of prostate histology

Gleason patterns of prostate cancer histopathology, characterized primarily by morphological and architectural attributes of histological structures (glands and nuclei), have been found to be highly correlated with disease aggressiveness and patient outcome. Gleason patterns 4 and 5 are highly correlated with more aggressive disease and poorer patient outcome, while Gleason patterns 1-3 tend to reflect more favorable patient outcome. Because Gleason grading is done manually by a pathologist visually examining glass (or digital) slides subtle morphologic and architectural differences of histological attributes, in addition to other factors, may result in grading errors and hence cause high inter-observer variability. Recently some researchers have proposed computerized decision support systems to automatically grade Gleason patterns by using features pertaining to nuclear architecture, gland morphology, as well as tissue texture. Automated characterization of gland morphology has been shown to distinguish between intermediate Gleason patterns 3 and 4 with high accuracy. Manifold learning (ML) schemes attempt to generate a low dimensional manifold representation of a higher dimensional feature space while simultaneously preserving nonlinear relationships between object instances. Classification can then be performed in the low dimensional space with high accuracy. However ML is sensitive to the samples contained in the dataset; changes in the dataset may alter the manifold structure. In this paper we present a manifold regularization technique to constrain the low dimensional manifold to a specific range of possible manifold shapes, the range being determined via a statistical shape model of manifolds (SSMM). In this work we demonstrate applications of the SSMM in (1) identifying samples on the manifold which contain noise, defined as those samples which deviate from the SSMM, and (2) accurate out-of-sample extrapolation (OSE) of newly acquired samples onto a manifold constrained by the SSMM. We demonstrate these applications of the SSMM in the context of distinguish between Gleason patterns 3 and 4 using glandular morphologic features in a prostate histopathology dataset of 58 patient studies. Identifying and eliminating noisy samples from the manifold via the SSMM results in a statistically significant improvement in area under the receiver operator characteristic curve (AUC), 0.832 ± 0.048 with removal of noisy samples compared to a AUC of 0.779 ± 0.075 without removal of samples. The use of the SSMM for OSE of newly acquired glands also shows statistically significant improvement in AUC, 0.834 ± 0.051 with the SSMM compared to 0.779 ± 0.054 without the SSMM. Similar results were observed for the synthetic Swiss Roll and Helix datasets.