How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities

The cell is arguably the smallest unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells. Here we propose a vision of AI-powered Virtual Cells, where robust representations of cells and cellular systems under different conditions are directly learned from growing biological data across measurements and scales. We discuss desired capabilities of AI Virtual Cells, including generating universal representations of biological entities across scales, and facilitating interpretable in silico experiments to predict and understand their behavior using Virtual Instruments. We further address the challenges, opportunities and requirements to realize this vision including data needs, evaluation strategies, and community standards and engagement to ensure biological accuracy and broad utility. We envision a future where AI Virtual Cells help identify new drug targets, predict cellular responses to perturbations, as well as scale hypothesis exploration. With open science collaborations across the biomedical ecosystem that includes academia, philanthropy, and the biopharma and AI industries, a comprehensive predictive understanding of cell mechanisms and interactions is within reach.

Automated Statistical Model Discovery with Language Models

Statistical model discovery involves a challenging search over a vast space of models subject to domain-specific modeling constraints. Efficiently searching over this space requires human expertise in modeling and the problem domain. Motivated by the domain knowledge and programming capabilities of large language models (LMs), we introduce a method for language model driven automated statistical model discovery. We cast our automated procedure within the framework of Box's Loop: the LM iterates between proposing statistical models represented as probabilistic programs, acting as a modeler, and critiquing those models, acting as a domain expert. By leveraging LMs, we do not have to define a domain-specific language of models or design a handcrafted search procedure, key restrictions of previous systems. We evaluate our method in three common settings in probabilistic modeling: searching within a restricted space of models, searching over an open-ended space, and improving classic models under natural language constraints (e.g., this model should be interpretable to an ecologist). Our method matches the performance of previous systems, identifies models on par with human expert designed models, and extends classic models in interpretable ways. Our results highlight the promise of LM driven model discovery.

Hybrid Square Neural ODE Causal Modeling

Hybrid models combine mechanistic ODE-based dynamics with flexible and expressive neural network components. Such models have grown rapidly in popularity, especially in scientific domains where such ODE-based modeling offers important interpretability and validated causal grounding (e.g., for counterfactual reasoning). The incorporation of mechanistic models also provides inductive bias in standard blackbox modeling approaches, critical when learning from small datasets or partially observed, complex systems. Unfortunately, as hybrid models become more flexible, the causal grounding provided by the mechanistic model can quickly be lost. We address this problem by leveraging another common source of domain knowledge: ranking of treatment effects for a set of interventions, even if the precise treatment effect is unknown. We encode this information in a causal loss that we combine with the standard predictive loss to arrive at a hybrid loss that biases our learning towards causally valid hybrid models. We demonstrate our ability to achieve a win-win -- state-of-the-art predictive performance and causal validity -- in the challenging task of modeling glucose dynamics during exercise.

Interpretable Mechanistic Representations for Meal-level Glycemic Control in the Wild

Diabetes encompasses a complex landscape of glycemic control that varies widely among individuals. However, current methods do not faithfully capture this variability at the meal level. On the one hand, expert-crafted features lack the flexibility of data-driven methods; on the other hand, learned representations tend to be uninterpretable which hampers clinical adoption. In this paper, we propose a hybrid variational autoencoder to learn interpretable representations of CGM and meal data. Our method grounds the latent space to the inputs of a mechanistic differential equation, producing embeddings that reflect physiological quantities, such as insulin sensitivity, glucose effectiveness, and basal glucose levels. Moreover, we introduce a novel method to infer the glucose appearance rate, making the mechanistic model robust to unreliable meal logs. On a dataset of CGM and self-reported meals from individuals with type-2 diabetes and pre-diabetes, our unsupervised representation discovers a separation between individuals proportional to their disease severity. Our embeddings produce clusters that are up to 4x better than naive, expert, black-box, and pure mechanistic features. Our method provides a nuanced, yet interpretable, embedding space to compare glycemic control within and across individuals, directly learnable from in-the-wild data.

Sequence Modeling with Multiresolution Convolutional Memory

Efficiently capturing the long-range patterns in sequential data sources salient to a given task -- such as classification and generative modeling -- poses a fundamental challenge. Popular approaches in the space tradeoff between the memory burden of brute-force enumeration and comparison, as in transformers, the computational burden of complicated sequential dependencies, as in recurrent neural networks, or the parameter burden of convolutional networks with many or large filters. We instead take inspiration from wavelet-based multiresolution analysis to define a new building block for sequence modeling, which we call a MultiresLayer. The key component of our model is the multiresolution convolution, capturing multiscale trends in the input sequence. Our MultiresConv can be implemented with shared filters across a dilated causal convolution tree. Thus it garners the computational advantages of convolutional networks and the principled theoretical motivation of wavelet decompositions. Our MultiresLayer is straightforward to implement, requires significantly fewer parameters, and maintains at most a $\mathcal{O}(N\log N)$ memory footprint for a length $N$ sequence. Yet, by stacking such layers, our model yields state-of-the-art performance on a number of sequence classification and autoregressive density estimation tasks using CIFAR-10, ListOps, and PTB-XL datasets.

Learning Absorption Rates in Glucose-Insulin Dynamics from Meal Covariates

Traditional models of glucose-insulin dynamics rely on heuristic parameterizations chosen to fit observations within a laboratory setting. However, these models cannot describe glucose dynamics in daily life. One source of failure is in their descriptions of glucose absorption rates after meal events. A meal's macronutritional content has nuanced effects on the absorption profile, which is difficult to model mechanistically. In this paper, we propose to learn the effects of macronutrition content from glucose-insulin data and meal covariates. Given macronutrition information and meal times, we use a neural network to predict an individual's glucose absorption rate. We use this neural rate function as the control function in a differential equation of glucose dynamics, enabling end-to-end training. On simulated data, our approach is able to closely approximate true absorption rates, resulting in better forecast than heuristic parameterizations, despite only observing glucose, insulin, and macronutritional information. Our work readily generalizes to meal events with higher-dimensional covariates, such as images, setting the stage for glucose dynamics models that are personalized to each individual's daily life.

Granger Causality: A Review and Recent Advances

Introduced more than a half century ago, Granger causality has become a popular tool for analyzing time series data in many application domains, from economics and finance to genomics and neuroscience. Despite this popularity, the validity of this notion for inferring causal relationships among time series has remained the topic of continuous debate. Moreover, while the original definition was general, limitations in computational tools have primarily limited the applications of Granger causality to simple bivariate vector auto-regressive processes or pairwise relationships among a set of variables. Starting with a review of early developments and debates, this paper discusses recent advances that address various shortcomings of the earlier approaches, from models for high-dimensional time series to more recent developments that account for nonlinear and non-Gaussian observations and allow for sub-sampled and mixed frequency time series.

Model-based metrics: Sample-efficient estimates of predictive model subpopulation performance

Machine learning models $-$ now commonly developed to screen, diagnose, or predict health conditions $-$ are evaluated with a variety of performance metrics. An important first step in assessing the practical utility of a model is to evaluate its average performance over an entire population of interest. In many settings, it is also critical that the model makes good predictions within predefined subpopulations. For instance, showing that a model is fair or equitable requires evaluating the model's performance in different demographic subgroups. However, subpopulation performance metrics are typically computed using only data from that subgroup, resulting in higher variance estimates for smaller groups. We devise a procedure to measure subpopulation performance that can be more sample-efficient than the typical subsample estimates. We propose using an evaluation model $-$ a model that describes the conditional distribution of the predictive model score $-$ to form model-based metric (MBM) estimates. Our procedure incorporates model checking and validation, and we propose a computationally efficient approximation of the traditional nonparametric bootstrap to form confidence intervals. We evaluate MBMs on two main tasks: a semi-synthetic setting where ground truth metrics are available and a real-world hospital readmission prediction task. We find that MBMs consistently produce more accurate and lower variance estimates of model performance for small subpopulations.

Breiman's two cultures: You don't have to choose sides

Breiman's classic paper casts data analysis as a choice between two cultures: data modelers and algorithmic modelers. Stated broadly, data modelers use simple, interpretable models with well-understood theoretical properties to analyze data. Algorithmic modelers prioritize predictive accuracy and use more flexible function approximations to analyze data. This dichotomy overlooks a third set of models $-$ mechanistic models derived from scientific theories (e.g., ODE/SDE simulators). Mechanistic models encode application-specific scientific knowledge about the data. And while these categories represent extreme points in model space, modern computational and algorithmic tools enable us to interpolate between these points, producing flexible, interpretable, and scientifically-informed hybrids that can enjoy accurate and robust predictions, and resolve issues with data analysis that Breiman describes, such as the Rashomon effect and Occam's dilemma. Challenges still remain in finding an appropriate point in model space, with many choices on how to compose model components and the degree to which each component informs inferences.

Representing and Denoising Wearable ECG Recordings

Modern wearable devices are embedded with a range of noninvasive biomarker sensors that hold promise for improving detection and treatment of disease. One such sensor is the single-lead electrocardiogram (ECG) which measures electrical signals in the heart. The benefits of the sheer volume of ECG measurements with rich longitudinal structure made possible by wearables come at the price of potentially noisier measurements compared to clinical ECGs, e.g., due to movement. In this work, we develop a statistical model to simulate a structured noise process in ECGs derived from a wearable sensor, design a beat-to-beat representation that is conducive for analyzing variation, and devise a factor analysis-based method to denoise the ECG. We study synthetic data generated using a realistic ECG simulator and a structured noise model. At varying levels of signal-to-noise, we quantitatively measure an upper bound on performance and compare estimates from linear and non-linear models. Finally, we apply our method to a set of ECGs collected by wearables in a mobile health study.