MOTIVATION: Tumorigenesis is an evolutionary process by which tumor cells acquire sequences of mutations leading to increased growth, invasiveness and eventually metastasis. It is hoped that by identifying the common patterns of mutations underlying major cancer sub-types, we can better understand the molecular basis of tumor development and identify new diagnostics and therapeutic targets. This goal has motivated several attempts to apply evolutionary tree reconstruction methods to assays of tumor state. Inference of tumor evolution is in principle aided by the fact that tumors are heterogeneous, retaining remnant populations of different stages along their development along with contaminating healthy cell populations. In practice, though, this heterogeneity complicates interpretation of tumor data because distinct cell types are conflated by common methods for assaying the tumor state. We previously proposed a method to computationally infer cell populations from measures of tumor-wide gene expression through a geometric interpretation of mixture type separation, but this approach deals poorly with noisy and outlier data. RESULTS: In the present work, we propose a new method to perform tumor mixture separation efficiently and robustly to an experimental error. The method builds on the prior geometric approach but uses a novel objective function allowing for robust fits that greatly reduces the sensitivity to noise and outliers. We further develop an efficient gradient optimization method to optimize this 'soft geometric unmixing' objective for measurements of tumor DNA copy numbers assessed by array comparative genomic hybridization (aCGH) data. We show, on a combination of semi-synthetic and real data, that the method yields fast and accurate separation of tumor states. CONCLUSIONS: We have shown a novel objective function and optimization method for the robust separation of tumor sub-types from aCGH data and have shown that the method provides fast, accurate reconstruction of tumor states from mixed samples. Better solutions to this problem can be expected to improve our ability to accurately identify genetic abnormalities in primary tumor samples and to infer patterns of tumor evolution. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

We introduce a family of spectral partitioning methods. Edge separators of a graph are produced by iteratively reweighting the edges until the graph disconnects into the prescribed number of components. At each iteration a small number of eigenvectors with small eigenvalue are computed and used to determine the reweighting. In this way spectral rounding directly produces discrete solutions where as current spectral algorithms must map the continuous eigenvectors to discrete solutions by employing a heuristic geometric separator (e.g. k-means). We show that spectral rounding compares favorably to current spectral approximations on the Normalized Cut criterion (NCut). Results are given for natural image segmentation, medical image segmentation, and clustering. A practical version is shown to converge.

We optimize over the set of corrected Laplacians (CL) associated with a weighted graph to improve the average case normalized cut (NCut) of a graph. Unlike edge-relaxation SDPs, optimizing over the set CL naturally exploits the matrix sparsity by operating solely on the diagonal. This structure is critical to image segmentation applications because the number of vertices is generally proportional to the number of pixels in the image. CL optimization provides a guiding principle for improving the combinatorial solution over the spectral relaxation, which is important because small improvements in the cut cost often result in significant improvements in the perceptual relevance of the segmentation. We develop an optimization procedure to accommodate prior information in the form of statistical shape models, resulting in a segmentation method that produces foreground regions which are consistent with a parameterized family of shapes. We validate our technique with ground truth on MRI medical images, providing a quantitative comparison against results produced by current spectral relaxation approaches to graph partitioning.