Parallel Implementation of Efficient Search Schemes for the Inference of Cancer Progression Models

The emergence and development of cancer is a consequence of the accumulation over time of genomic mutations involving a specific set of genes, which provides the cancer clones with a functional selective advantage. In this work, we model the order of accumulation of such mutations during the progression, which eventually leads to the disease, by means of probabilistic graphic models, i.e., Bayesian Networks (BNs). We investigate how to perform the task of learning the structure of such BNs, according to experimental evidence, adopting a global optimization meta-heuristics. In particular, in this work we rely on Genetic Algorithms, and to strongly reduce the execution time of the inference -- which can also involve multiple repetitions to collect statistically significant assessments of the data -- we distribute the calculations using both multi-threading and a multi-node architecture. The results show that our approach is characterized by good accuracy and specificity; we also demonstrate its feasibility, thanks to a 84x reduction of the overall execution time with respect to a traditional sequential implementation

Efficient computational strategies to learn the structure of probabilistic graphical models of cumulative phenomena

Structural learning of Bayesian Networks (BNs) is a NP-hard problem, which is further complicated by many theoretical issues, such as the I-equivalence among different structures. In this work, we focus on a specific subclass of BNs, named Suppes-Bayes Causal Networks (SBCNs), which include specific structural constraints based on Suppes' probabilistic causation to efficiently model cumulative phenomena. Here we compare the performance, via extensive simulations, of various state-of-the-art search strategies, such as local search techniques and Genetic Algorithms, as well as of distinct regularization methods. The assessment is performed on a large number of simulated datasets from topologies with distinct levels of complexity, various sample size and different rates of errors in the data. Among the main results, we show that the introduction of Suppes' constraints dramatically improve the inference accuracy, by reducing the solution space and providing a temporal ordering on the variables. We also report on trade-offs among different search techniques that can be efficiently employed in distinct experimental settings. This manuscript is an extended version of the paper "Structural Learning of Probabilistic Graphical Models of Cumulative Phenomena" presented at the 2018 International Conference on Computational Science

Multi-objective optimization to explicitly account for model complexity when learning Bayesian Networks

Bayesian Networks have been widely used in the last decades in many fields, to describe statistical dependencies among random variables. In general, learning the structure of such models is a problem with considerable theoretical interest that still poses many challenges. On the one hand, this is a well-known NP-complete problem, which is practically hardened by the huge search space of possible solutions. On the other hand, the phenomenon of I-equivalence, i.e., different graphical structures underpinning the same set of statistical dependencies, may lead to multimodal fitness landscapes further hindering maximum likelihood approaches to solve the task. Despite all these difficulties, greedy search methods based on a likelihood score coupled with a regularization term to account for model complexity, have been shown to be surprisingly effective in practice. In this paper, we consider the formulation of the task of learning the structure of Bayesian Networks as an optimization problem based on a likelihood score. Nevertheless, our approach do not adjust this score by means of any of the complexity terms proposed in the literature; instead, it accounts directly for the complexity of the discovered solutions by exploiting a multi-objective optimization procedure. To this extent, we adopt NSGA-II and define the first objective function to be the likelihood of a solution and the second to be the number of selected arcs. We thoroughly analyze the behavior of our method on a wide set of simulated data, and we discuss the performance considering the goodness of the inferred solutions both in terms of their objective functions and with respect to the retrieved structure. Our results show that NSGA-II can converge to solutions characterized by better likelihood and less arcs than classic approaches, although paradoxically frequently characterized by a lower similarity to the target network

Learning mutational graphs of individual tumour evolution from single-cell and multi-region sequencing data

Background. A large number of algorithms is being developed to reconstruct evolutionary models of individual tumours from genome sequencing data. Most methods can analyze multiple samples collected either through bulk multi-region sequencing experiments or the sequencing of individual cancer cells. However, rarely the same method can support both data types. Results. We introduce TRaIT, a computational framework to infer mutational graphs that model the accumulation of multiple types of somatic alterations driving tumour evolution. Compared to other tools, TRaIT supports multi-region and single-cell sequencing data within the same statistical framework, and delivers expressive models that capture many complex evolutionary phenomena. TRaIT improves accuracy, robustness to data-specific errors and computational complexity compared to competing methods. Conclusions. We show that the application of TRaIT to single-cell and multi-region cancer datasets can produce accurate and reliable models of single-tumour evolution, quantify the extent of intra-tumour heterogeneity and generate new testable experimental hypotheses