Toward AI-Driven Digital Organism: Multiscale Foundation Models for Predicting, Simulating and Programming Biology at All Levels

We present an approach of using AI to model and simulate biology and life. Why is it important? Because at the core of medicine, pharmacy, public health, longevity, agriculture and food security, environmental protection, and clean energy, it is biology at work. Biology in the physical world is too complex to manipulate and always expensive and risky to tamper with. In this perspective, we layout an engineering viable approach to address this challenge by constructing an AI-Driven Digital Organism (AIDO), a system of integrated multiscale foundation models, in a modular, connectable, and holistic fashion to reflect biological scales, connectedness, and complexities. An AIDO opens up a safe, affordable and high-throughput alternative platform for predicting, simulating and programming biology at all levels from molecules to cells to individuals. We envision that an AIDO is poised to trigger a new wave of better-guided wet-lab experimentation and better-informed first-principle reasoning, which can eventually help us better decode and improve life.

Causal Representation Learning from Multimodal Biological Observations

Prevalent in biological applications (e.g., human phenotype measurements), multimodal datasets can provide valuable insights into the underlying biological mechanisms. However, current machine learning models designed to analyze such datasets still lack interpretability and theoretical guarantees, which are essential to biological applications. Recent advances in causal representation learning have shown promise in uncovering the interpretable latent causal variables with formal theoretical certificates. Unfortunately, existing works for multimodal distributions either rely on restrictive parametric assumptions or provide rather coarse identification results, limiting their applicability to biological research which favors a detailed understanding of the mechanisms. In this work, we aim to develop flexible identification conditions for multimodal data and principled methods to facilitate the understanding of biological datasets. Theoretically, we consider a flexible nonparametric latent distribution (c.f., parametric assumptions in prior work) permitting causal relationships across potentially different modalities. We establish identifiability guarantees for each latent component, extending the subspace identification results from prior work. Our key theoretical ingredient is the structural sparsity of the causal connections among distinct modalities, which, as we will discuss, is natural for a large collection of biological systems. Empirically, we propose a practical framework to instantiate our theoretical insights. We demonstrate the effectiveness of our approach through extensive experiments on both numerical and synthetic datasets. Results on a real-world human phenotype dataset are consistent with established medical research, validating our theoretical and methodological framework.

Generative AI Enables Medical Image Segmentation in Ultra Low-Data Regimes

Semantic segmentation of medical images is pivotal in applications like disease diagnosis and treatment planning. While deep learning has excelled in automating this task, a major hurdle is the need for numerous annotated segmentation masks, which are resource-intensive to produce due to the required expertise and time. This scenario often leads to ultra low-data regimes, where annotated images are extremely limited, posing significant challenges for the generalization of conventional deep learning methods on test images. To address this, we introduce a generative deep learning framework, which uniquely generates high-quality paired segmentation masks and medical images, serving as auxiliary data for training robust models in data-scarce environments. Unlike traditional generative models that treat data generation and segmentation model training as separate processes, our method employs multi-level optimization for end-to-end data generation. This approach allows segmentation performance to directly influence the data generation process, ensuring that the generated data is specifically tailored to enhance the performance of the segmentation model. Our method demonstrated strong generalization performance across 9 diverse medical image segmentation tasks and on 16 datasets, in ultra-low data regimes, spanning various diseases, organs, and imaging modalities. When applied to various segmentation models, it achieved performance improvements of 10-20\% (absolute), in both same-domain and out-of-domain scenarios. Notably, it requires 8 to 20 times less training data than existing methods to achieve comparable results. This advancement significantly improves the feasibility and cost-effectiveness of applying deep learning in medical imaging, particularly in scenarios with limited data availability.

From Glucose Patterns to Health Outcomes: A Generalizable Foundation Model for Continuous Glucose Monitor Data Analysis

Recent advances in self-supervised learning enabled novel medical AI models, known as foundation models (FMs) that offer great potential for characterizing health from diverse biomedical data. Continuous glucose monitoring (CGM) provides rich, temporal data on glycemic patterns, but its full potential for predicting broader health outcomes remains underutilized. Here, we present GluFormer, a generative foundation model on biomedical temporal data based on a transformer architecture, and trained on over 10 million CGM measurements from 10,812 non-diabetic individuals. We tokenized the CGM training data and trained GluFormer using next token prediction in a generative, autoregressive manner. We demonstrate that GluFormer generalizes effectively to 15 different external datasets, including 4936 individuals across 5 different geographical regions, 6 different CGM devices, and several metabolic disorders, including normoglycemic, prediabetic, and diabetic populations, as well as those with gestational diabetes and obesity. GluFormer produces embeddings which outperform traditional CGM analysis tools, and achieves high Pearson correlations in predicting clinical parameters such as HbA1c, liver-related parameters, blood lipids, and sleep-related indices. Notably, GluFormer can also predict onset of future health outcomes even 4 years in advance. We also show that CGM embeddings from pre-intervention periods in Randomized Clinical Trials (RCTs) outperform other methods in predicting primary and secondary outcomes. When integrating dietary data into GluFormer, we show that the enhanced model can accurately generate CGM data based only on dietary intake data, simulate outcomes of dietary interventions, and predict individual responses to specific foods. Overall, we show that GluFormer accurately predicts health outcomes which generalize across different populations metabolic conditions.

A Multimodal Dataset of 21,412 Recorded Nights for Sleep and Respiratory Research

This study introduces a novel, rich dataset obtained from home sleep apnea tests using the FDA-approved WatchPAT-300 device, collected from 7,077 participants over 21,412 nights. The dataset comprises three levels of sleep data: raw multi-channel time-series from sensors, annotated sleep events, and computed summary statistics, which include 447 features related to sleep architecture, sleep apnea, and heart rate variability (HRV). We present reference values for Apnea/Hypopnea Index (AHI), sleep efficiency, Wake After Sleep Onset (WASO), and HRV sample entropy, stratified by age and sex. Moreover, we demonstrate that the dataset improves the predictive capability for various health related traits, including body composition, bone density, blood sugar levels and cardiovascular health. These results illustrate the dataset's potential to advance sleep research, personalized healthcare, and machine learning applications in biomedicine.

Regularization Learning Networks: Deep Learning for Tabular Datasets

Despite their impressive performance, Deep Neural Networks (DNNs) typically underperform Gradient Boosting Trees (GBTs) on many tabular-dataset learning tasks. We propose that applying a different regularization coefficient to each weight might boost the performance of DNNs by allowing them to make more use of the more relevant inputs. However, this will lead to an intractable number of hyperparameters. Here, we introduce Regularization Learning Networks (RLNs), which overcome this challenge by introducing an efficient hyperparameter tuning scheme which minimizes a new Counterfactual Loss. Our results show that RLNs significantly improve DNNs on tabular datasets, and achieve comparable results to GBTs, with the best performance achieved with an ensemble that combines GBTs and RLNs. RLNs produce extremely sparse networks, eliminating up to 99.8% of the network edges and 82% of the input features, thus providing more interpretable models and reveal the importance that the network assigns to different inputs. RLNs could efficiently learn a single network in datasets that comprise both tabular and unstructured data, such as in the setting of medical imaging accompanied by electronic health records. An open source implementation of RLN can be found at https://github.com/irashavitt/regularization_learning_networks.

Exact Inference in Networks with Discrete Children of Continuous Parents

Many real life domains contain a mixture of discrete and continuous variables and can be modeled as hybrid Bayesian Networks. Animportant subclass of hybrid BNs are conditional linear Gaussian (CLG) networks, where the conditional distribution of the continuous variables given an assignment to the discrete variables is a multivariate Gaussian. Lauritzen's extension to the clique tree algorithm can be used for exact inference in CLG networks. However, many domains also include discrete variables that depend on continuous ones, and CLG networks do not allow such dependencies to berepresented. No exact inference algorithm has been proposed for these enhanced CLG networks. In this paper, we generalize Lauritzen's algorithm, providing the first "exact" inference algorithm for augmented CLG networks - networks where continuous nodes are conditional linear Gaussians but that also allow discrete children ofcontinuous parents. Our algorithm is exact in the sense that it computes the exact distributions over the discrete nodes, and the exact first and second moments of the continuous ones, up to the accuracy obtained by numerical integration used within thealgorithm. When the discrete children are modeled with softmax CPDs (as is the case in many real world domains) the approximation of the continuous distributions using the first two moments is particularly accurate. Our algorithm is simple to implement and often comparable in its complexity to Lauritzen's algorithm. We show empirically that it achieves substantially higher accuracy than previous approximate algorithms.

Learning Module Networks

Methods for learning Bayesian network structure can discover dependency structure between observed variables, and have been shown to be useful in many applications. However, in domains that involve a large number of variables, the space of possible network structures is enormous, making it difficult, for both computational and statistical reasons, to identify a good model. In this paper, we consider a solution to this problem, suitable for domains where many variables have similar behavior. Our method is based on a new class of models, which we call module networks. A module network explicitly represents the notion of a module - a set of variables that have the same parents in the network and share the same conditional probability distribution. We define the semantics of module networks, and describe an algorithm that learns a module network from data. The algorithm learns both the partitioning of the variables into modules and the dependency structure between the variables. We evaluate our algorithm on synthetic data, and on real data in the domains of gene expression and the stock market. Our results show that module networks generalize better than Bayesian networks, and that the learned module network structure reveals regularities that are obscured in learned Bayesian networks.