We introduce an online outlier detection algorithm to detect outliers in a sequentially observed data stream. For this purpose, we use a two-stage filtering and hedging approach. In the first stage, we construct a multimodal probability density function to model the normal samples. In the second stage, given a new observation, we label it as an anomaly if the value of aforementioned density function is below a specified threshold at the newly observed point. In order to construct our multimodal density function, we use an incremental decision tree to construct a set of subspaces of the observation space. We train a single component density function of the exponential family using the observations, which fall inside each subspace represented on the tree. These single component density functions are then adaptively combined to produce our multimodal density function, which is shown to achieve the performance of the best convex combination of the density functions defined on the subspaces. As we observe more samples, our tree grows and produces more subspaces. As a result, our modeling power increases in time, while mitigating overfitting issues. In order to choose our threshold level to label the observations, we use an adaptive thresholding scheme. We show that our adaptive threshold level achieves the performance of the optimal prefixed threshold level, which knows the observation labels in hindsight. Our algorithm provides significant performance improvements over the state of the art in our wide set of experiments involving both synthetic as well as real data.

Identification of mutations of the genes that give cancer a selective advantage is an important step towards research and clinical objectives. As such, there has been a growing interest in developing methods for identification of driver genes and their temporal order within a single patient (intra-tumor) as well as across a cohort of patients (inter-tumor). In this paper, we develop a probabilistic model for tumor progression, in which the driver genes are clustered into several ordered driver pathways. We develop an efficient inference algorithm that exhibits favorable scalability to the number of genes and samples compared to a previously introduced ILP-based method. Adopting a probabilistic approach also allows principled approaches to model selection and uncertainty quantification. Using a large set of experiments on synthetic datasets, we demonstrate our superior performance compared to the ILP-based method. We also analyze two biological datasets of colorectal and glioblastoma cancers. We emphasize that while the ILP-based method puts many seemingly passenger genes in the driver pathways, our algorithm keeps focused on truly driver genes and outputs more accurate models for cancer progression.

Identifying the interrelations among cancer driver genes and the patterns in which the driver genes get mutated is critical for understanding cancer. In this paper, we study cross-sectional data from cohorts of tumors to identify the cancer-type (or subtype) specific process in which the cancer driver genes accumulate critical mutations. We model this mutation accumulation process using a tree, where each node includes a driver gene or a set of driver genes. A mutation in each node enables its children to have a chance of mutating. This model simultaneously explains the mutual exclusivity patterns observed in mutations in specific cancer genes (by its nodes) and the temporal order of events (by its edges). We introduce a computationally efficient dynamic programming procedure for calculating the likelihood of our noisy datasets and use it to build our Markov Chain Monte Carlo (MCMC) inference algorithm, ToMExO. Together with a set of engineered MCMC moves, our fast likelihood calculations enable us to work with datasets with hundreds of genes and thousands of tumors, which cannot be dealt with using available cancer progression analysis methods. We demonstrate our method’s performance on several synthetic datasets covering various scenarios for cancer progression dynamics. Then, a comparison against two state-of-the-art methods on a moderate-size biological dataset shows the merits of our algorithm in identifying significant and valid patterns. Finally, we present our analyses of several large biological datasets, including colorectal cancer, glioblastoma, and pancreatic cancer. In all the analyses, we validate the results using a set of method-independent metrics testing the causality and significance of the relations identified by ToMExO or competing methods.