Unsupervised logic-based mechanism inference for network-driven biological processes

Abstract

Modern analytical techniques enable researchers to collect data about cellular states, before and after perturbations. These states can be characterized using analytical techniques, but the inference of regulatory interactions that explain and predict changes in these states remains a challenge. Here we present a generalizable unsupervised approach to generate parameter-free, logic-based mechanistic hypotheses of cellular processes, described by multiple discrete states. Our algorithm employs a Hamming-distance based approach to formulate, test, and identify, the best mechanism that links two states. Our approach comprises two steps. First, a model with no prior knowledge except for the mapping between initial and attractor states is built. Second, we employ biological constraints to improve model fidelity. Our algorithm automatically recovers the relevant dynamics for the explored models and recapitulates all aspects of the original models biochemical species concentration dynamics. We then conclude by placing our results in the context of ongoing work in the field and discuss how our approach could be used to infer mechanisms of signaling, gene-regulatory, and any other input-output processes describable by logic-based mechanisms.

A dynamical low-rank approach to solve the chemical master equation for biological reaction networks

“…In this formalism, each biochemical species (e.g. genes, proteins) can exist in two states (on or off), which significantly simplifies model complexity and only requires that one knows the structure of the network (which in some situations can be inferred from data [23]). The state of the network is then determined by a binary string that encodes which species are switched on and which are switched off.…”