arXiv subjects

Daniele Ramazzotti

Publications and source records attributed to Daniele Ramazzotti.

24 records · Page 2Linked to original sources

arXiv2016

A Model of Selective Advantage for the Efficient Inference of Cancer Clonal Evolution

Recently, there has been a resurgence of interest in rigorous algorithms for the inference of cancer progression from genomic data. The motivations are manifold: (i) growing NGS and single cell data from cancer patients, (ii) need for novel Data Science and Machine Learning algorithms to infer models of cancer progression, and (iii) a desire to understand the temporal and heterogeneous structure of tumor to tame its progression by efficacious therapeutic intervention. This thesis presents a multi-disciplinary effort to model tumor progression involving successive accumulation of genetic alterations, each resulting populations manifesting themselves in a cancer phenotype. The framework presented in this work along with algorithms derived from it, represents a novel approach for inferring cancer progression, whose accuracy and convergence rates surpass the existing techniques. The approach derives its power from several fields including algorithms in machine learning, theory of causality and cancer biology. Furthermore, a modular pipeline to extract ensemble-level progression models from sequenced cancer genomes is proposed. The pipeline combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations and progression model inference. Furthermore, the results are validated by synthetic data with realistic generative models, and empirically interpreted in the context of real cancer datasets; in the later case, biologically significant conclusions are also highlighted. Specifically, it demonstrates the pipeline's ability to reproduce much of the knowledge on colorectal cancer, as well as to suggest novel hypotheses. Lastly, it also proves that the proposed framework can be applied to reconstruct the evolutionary history of cancer clones in single patients, as illustrated by an example from clear cell renal carcinomas.

cs.LG↗

arXiv2016

TRONCO: an R package for the inference of cancer progression models from heterogeneous genomic data

Motivation: We introduce TRONCO (TRanslational ONCOlogy), an open-source R package that implements the state-of-the-art algorithms for the inference of cancer progression models from (epi)genomic mutational profiles. TRONCO can be used to extract population-level models describing the trends of accumulation of alterations in a cohort of cross-sectional samples, e.g., retrieved from publicly available databases, and individual-level models that reveal the clonal evolutionary history in single cancer patients, when multiple samples, e.g., multiple biopsies or single-cell sequencing data, are available. The resulting models can provide key hints in uncovering the evolutionary trajectories of cancer, especially for precision medicine or personalized therapy. Availability: TRONCO is released under the GPL license, it is hosted in the Software section at http://bimib.disco.unimib.it/ and archived also at bioconductor.org. Contact: tronco@disco.unimib.it

q-bio.QM↗

arXiv2015

CAPRI: Efficient Inference of Cancer Progression Models from Cross-sectional Data

We devise a novel inference algorithm to effectively solve the cancer progression model reconstruction problem. Our empirical analysis of the accuracy and convergence rate of our algorithm, CAncer PRogression Inference (CAPRI), shows that it outperforms the state-of-the-art algorithms addressing similar problems. Motivation: Several cancer-related genomic data have become available (e.g., The Cancer Genome Atlas, TCGA) typically involving hundreds of patients. At present, most of these data are aggregated in a cross-sectional fashion providing all measurements at the time of diagnosis.Our goal is to infer cancer progression models from such data. These models are represented as directed acyclic graphs (DAGs) of collections of selectivity relations, where a mutation in a gene A selects for a later mutation in a gene B. Gaining insight into the structure of such progressions has the potential to improve both the stratification of patients and personalized therapy choices. Results: The CAPRI algorithm relies on a scoring method based on a probabilistic theory developed by Suppes, coupled with bootstrap and maximum likelihood inference. The resulting algorithm is efficient, achieves high accuracy, and has good complexity, also, in terms of convergence properties. CAPRI performs especially well in the presence of noise in the data, and with limited sample sizes. Moreover CAPRI, in contrast to other approaches, robustly reconstructs different types of confluent trajectories despite irregularities in the data.We also report on an ongoing investigation using CAPRI to study atypical Chronic Myeloid Leukemia, in which we uncovered non trivial selectivity relations and exclusivity patterns among key genomic events.

math.ST↗

arXiv2014

Inferring tree causal models of cancer progression with probability raising

Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges) to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models.

math.ST↗

arXiv2014

An Observational Study: The Effect of Diuretics Administration on Outcomes of Mortality and Mean Duration of I.C.U. Stay

This thesis conducts an observational study into whether diuretics should be administered to ICU patients with sepsis when length of stay in the ICU and 30-day post-hospital mortality are considered. The central contribution of the thesis is a stepwise, reusable software-based approach for examining the outcome of treatment vs no-treatment decisions with observational data. The thesis implements, demonstrates and draws findings via three steps: Step 1. Form a study group and prepare modeling variables. Step 2. Model the propensity of the study group with respect to the administration of diuretics with a propensity score function and create groups of patients balanced in this propensity. Step 3. Statistically model each outcome with study variables to decide whether the administration of diuretics has a significant impact. Additionally, the thesis presents a preliminary machine learning based method using Genetic Programming to predict mortality and length of stay in ICU outcomes for the study group. The thesis finds, for its study group, in three of five propensity balanced quintiles, a statistically significant longer length of stay when diuretics are administered. For a less sick subset of patients (SAPS ICU admission score < 17) the administration of diuretics has a significant negative effect on mortality.

stat.AP↗

arXiv2013

A Model of Colonic Crypts using SBML Spatial

The Spatial Processes package enables an explicit definition of a spatial environment on top of the normal dynamic modeling SBML capabilities. The possibility of an explicit representation of spatial dynamics increases the representation power of SBML. In this work we used those new SBML features to define an extensive model of colonic crypts composed of the main cellular types (from stem cells to fully differentiated cells), alongside their spatial dynamics.

cs.CE↗