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

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

Data-driven modelling of biological multi-scale processes

Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers