We introduce a comprehensive framework for modeling single cell transcriptomic responses to perturbations, aimed at standardizing benchmarking in this rapidly evolving field. Our approach includes a modular and user-friendly model development and evaluation platform, a collection of diverse perturbational datasets, and a set of metrics designed to fairly compare models and dissect their performance. Through extensive evaluation of both published and baseline models across diverse datasets, we highlight the limitations of widely used models, such as mode collapse. We also demonstrate the importance of rank metrics which complement traditional model fit measures, such as RMSE, for validating model effectiveness. Notably, our results show that while no single model architecture clearly outperforms others, simpler architectures are generally competitive and scale well with larger datasets. Overall, this benchmarking exercise sets new standards for model evaluation, supports robust model development, and furthers the use of these models to simulate genetic and chemical screens for therapeutic discovery.

Simulation models often lack tractable likelihood functions, making likelihood-free inference methods indispensable. Approximate Bayesian computation generates likelihood-free posterior samples by comparing simulated and observed data through some distance measure, but existing approaches are often poorly suited to time series simulators, for example due to an independent and identically distributed data assumption. In this paper, we propose to use path signatures in approximate Bayesian computation to handle the sequential nature of time series. We provide theoretical guarantees on the resultant posteriors and demonstrate competitive Bayesian parameter inference for simulators generating univariate, multivariate, and irregularly spaced sequences of non-iid data.

Simulation models of complex dynamics in the natural and social sciences commonly lack a tractable likelihood function, rendering traditional likelihood-based statistical inference impossible. Recent advances in machine learning have introduced novel algorithms for estimating otherwise intractable likelihood functions using a likelihood ratio trick based on binary classifiers. Consequently, efficient likelihood approximations can be obtained whenever good probabilistic classifiers can be constructed. We propose a kernel classifier for sequential data using path signatures based on the recently introduced signature kernel. We demonstrate that the representative power of signatures yields a highly performant classifier, even in the crucially important case where sample numbers are low. In such scenarios, our approach can outperform sophisticated neural networks for common posterior inference tasks.

Computer simulations have proven a valuable tool for understanding complex phenomena across the sciences. However, the utility of simulators for modelling and forecasting purposes is often restricted by low data quality, as well as practical limits to model fidelity. In order to circumvent these difficulties, we argue that modellers must treat simulators as idealistic representations of the true data generating process, and consequently should thoughtfully consider the risk of model misspecification. In this work we revisit neural posterior estimation (NPE), a class of algorithms that enable black-box parameter inference in simulation models, and consider the implication of a simulation-to-reality gap. While recent works have demonstrated reliable performance of these methods, the analyses have been performed using synthetic data generated by the simulator model itself, and have therefore only addressed the well-specified case. In this paper, we find that the presence of misspecification, in contrast, leads to unreliable inference when NPE is used naïvely. As a remedy we argue that principled scientific inquiry with simulators should incorporate a model criticism component, to facilitate interpretable identification of misspecification and a robust inference component, to fit ‘wrong but useful’ models. We propose robust neural posterior estimation (RNPE), an extension of NPE to simultaneously achieve both these aims, through explicitly modelling the discrepancies between simulations and the observed data. We assess the approach on a range of artificially misspecified examples, and find RNPE performs well across the tasks, whereas naïvely using NPE leads to misleading and erratic posteriors.

When the weights in a particle filter are not available analytically, standard resampling methods cannot be employed. To circumvent this problem state-of-the-art algorithms replace the true weights with non-negative unbiased estimates. This algorithm is still valid but at the cost of higher variance of the resulting filtering estimates in comparison to a particle filter using the true weights. We propose here a novel algorithm that allows for resampling according to the true intractable weights when only an unbiased estimator of the weights is available. We demonstrate our algorithm on several examples.