Bayesian causal inference of cell signal transduction from proteomics experiments

Cell signal transduction describes how a cell senses and processes signals from the environment using networks of interacting proteins. In computational systems biology, investigators apply machine learning methods for causal inference to develop causal Bayesian network models of signal transduction from experimental data. Directed edges in the network represent causal regulatory relationships, and the model can be used to predict the effects of interventions to signal transduction. Causal inference approaches applied to proteomics experiments use statistical associations between observed signaling protein concentrations to infer a causal Bayesian network model, but there is no experimental and analysis framework for applying these methods to this experimental context. The goal of this dissertation is to provide a Bayesian experimental design and modeling framework for causal inference of signal transduction. We evaluate how different high-throughput experimental settings affect the performance of algorithms that detect conditional dependence relationships between proteins. We present a Bayesian active learning approach for designing intervention experiments that reveal the direction of causal influence between proteins. Finally, we present a Bayesian model for inferring the parameters of the conditional probability density functions in a causal Bayesian network. The parameters are directly interpretable as a function of the rate constants in the biochemical reactions between interacting proteins. The work pays special attention to analysis of single-cell snapshot data such as mass cytometry, where each cell is a multivariate cell-level replicate of signal transduction at a single time point. We also address the role of large-scale bulk experiments such as mass-spectrometry-based proteomics, and small-scale time-course experiments in causal inference

Classification-based prediction of effective connectivity between timeseries with a realistic cortical network model

Effective connectivity measures the pattern of causal interactions between brain regions. Traditionally, these patterns of causality are inferred from brain recordings using either non-parametric, i.e., model-free, or parametric, i.e., model-based, approaches. The latter approaches, when based on biophysically plausible models, have the advantage that they may facilitate the interpretation of causality in terms of underlying neural mechanisms. Recent biophysically plausible neural network models of recurrent microcircuits have shown the ability to reproduce well the characteristics of real neural activity and can be applied to model interacting cortical circuits. Unfortunately, however, it is challenging to invert these models in order to estimate effective connectivity from observed data. Here, we propose to use a classification-based method to approximate the result of such complex model inversion. The classifier predicts the pattern of causal interactions given a multivariate timeseries as input. The classifier is trained on a large number of pairs of multivariate timeseries and the respective pattern of causal interactions, which are generated by simulation from the neural network model. In simulated experiments, we show that the proposed method is much more accurate in detecting the causal structure of timeseries than current best practice methods. Additionally, we present further results to characterize the validity of the neural network model and the ability of the classifier to adapt to the generative model of the data