Identifying mechanisms and therapeutic targets in muscle using Bayesian parameter estimation with conditional variational autoencoders

Abstract

Cardiomyopathies, often caused by mutations in genes encoding muscle proteins, are traditionally treated by phenotyping hearts and addressing symptoms post irreversible damage. With advancements in genotyping, early diagnosis is now possible, potentially introducing earlier treatment. However, the intricate structure of muscle and its myriad proteins make treatment predictions challenging. Here we approach the problem of estimating therapeutic targets for a mutation in mouse muscle using a spatially explicit half sarcomere muscle model. We selected 9 rate parameters in our model linked to both small molecules and cardiomyopathy-causing mutations. We then randomly varied these rate parameters and simulated an isometric twitch for each combination to generate a large training dataset. We used this dataset to train a Conditional Variational Autoencoder (CVAE), a technique used in Bayesian parameter estimation. Given simulated or experimental isometric twitches, this machine learning model is able to then predict the set of rate parameters which are most likely to yield that result. We then predict the set of rate parameters associated with twitches from control mice with the cardiac Troponin C (cTnC) I61Q variant and control twitches treated with the myosin activator Danicamtiv, as well as model parameters that recover the abnormal I61Q cTnC twitches. SIGNIFICANCEMachine learning techniques have potential to accelerate discoveries in biologically complex systems. However, they require large data sets and can be challenging in high dimensional systems such as cardiac muscle. In this study, we combined experimental measures of cardiac muscle twitch forces with mechanistic simulations and a newly developed mixture of Bayesian inference with neural networks (in autoencoders) to solve the inverse problem of determining the underlying kinetics for observed force generation by cardiac muscle. The autoencoders are trained on millions of simulations spanning parameter spaces that correspond to the mechanochemistry of cardiac sarcomeres. We apply the trained model to experimental data in order to infer parameters that can explain a diseased twitch and ways to recover it.