Modelling cancer progression using Mutual Hazard Networks.

MOTIVATION: Cancer progresses by accumulating genomic events, such as mutations and copy number alterations, whose chronological order is key to understanding the disease but difficult to observe. Instead, cancer progression models use co-occurrence patterns in cross-sectional data to infer epistatic interactions between events and thereby uncover their most likely order of occurrence. State-of-the-art progression models, however, are limited by mathematical tractability and only allow events to interact in directed acyclic graphs, to promote but not inhibit subsequent events, or to be mutually exclusive in distinct groups that cannot overlap. RESULTS: Here we propose Mutual Hazard Networks (MHN), a new Machine Learning algorithm to infer cyclic progression models from cross-sectional data. MHN model events by their spontaneous rate of fixation and by multiplicative effects they exert on the rates of successive events. MHN compared favourably to acyclic models in cross-validated model fit on four datasets tested. In application to the glioblastoma dataset from The Cancer Genome Atlas, MHN proposed a novel interaction in line with consecutive biopsies: IDH1 mutations are early events that promote subsequent fixation of TP53 mutations. AVAILABILITY AND IMPLEMENTATION: Implementation and data are available at https://github.com/RudiSchill/MHN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Loss-Function Learning for Digital Tissue Deconvolution.

The gene expression profile of a tissue averages the expression profiles of all cells in this tissue. Digital tissue deconvolution addresses the following inverse problem: given the expression profile y of a tissue, what is the cellular composition c of that tissue? If X is a matrix whose columns are reference profiles of individual cell types, the composition c can be computed by minimizing ℒ ( y - X c ) for a given loss function ℒ . Current methods use predefined all-purpose loss functions. They successfully quantify the dominating cells of a tissue, while often falling short in detecting small cell populations. In this study we use training data to learn the loss function ℒ along with the composition c . This allows us to adapt to application-specific requirements such as focusing on small cell populations or distinguishing phenotypically similar cell populations. Our method quantifies large cell fractions as accurately as existing methods and significantly improves the detection of small cell populations and the distinction of similar cell types.

DTD: An R Package for Digital Tissue Deconvolution.

Digital tissue deconvolution (DTD) estimates the cellular composition of a tissue from its bulk gene-expression profile. For this, DTD approximates the bulk as a mixture of cell-specific expression profiles. Different tissues have different cellular compositions, with cells in different activation states, and embedded in different environments. Consequently, DTD can profit from tailoring the deconvolution model to a specific tissue context. Loss-function learning adapts DTD to a specific tissue context, such as the deconvolution of blood, or a specific type of tumor tissue. We provide software for loss-function learning, for its validation and visualization, and for applying the DTD models to new data.

A multi-source data integration approach reveals novel associations between metabolites and renal outcomes in the German Chronic Kidney Disease study.

Omics data facilitate the gain of novel insights into the pathophysiology of diseases and, consequently, their diagnosis, treatment, and prevention. To this end, omics data are integrated with other data types, e.g., clinical, phenotypic, and demographic parameters of categorical or continuous nature. We exemplify this data integration issue for a chronic kidney disease (CKD) study, comprising complex clinical, demographic, and one-dimensional 1H nuclear magnetic resonance metabolic variables. Routine analysis screens for associations of single metabolic features with clinical parameters while accounting for confounders typically chosen by expert knowledge. This knowledge can be incomplete or unavailable. We introduce a framework for data integration that intrinsically adjusts for confounding variables. We give its mathematical and algorithmic foundation, provide a state-of-the-art implementation, and evaluate its performance by sanity checks and predictive performance assessment on independent test data. Particularly, we show that discovered associations remain significant after variable adjustment based on expert knowledge. In contrast, we illustrate that associations discovered in routine univariate screening approaches can be biased by incorrect or incomplete expert knowledge. Our data integration approach reveals important associations between CKD comorbidities and metabolites, including novel associations of the plasma metabolite trimethylamine-N-oxide with cardiac arrhythmia and infarction in CKD stage 3 patients.

Principles of Systems Biology, No. 31.

This month: selected work from the 2018 RECOMB meeting, organized by Ecole Polytechnique and held last April in Paris.