Starfysh integrates spatial transcriptomic and histologic data to reveal heterogeneous tumor-immune hubs.

Spatially resolved gene expression profiling provides insight into tissue organization and cell-cell crosstalk; however, sequencing-based spatial transcriptomics (ST) lacks single-cell resolution. Current ST analysis methods require single-cell RNA sequencing data as a reference for rigorous interpretation of cell states, mostly do not use associated histology images and are not capable of inferring shared neighborhoods across multiple tissues. Here we present Starfysh, a computational toolbox using a deep generative model that incorporates archetypal analysis and any known cell type markers to characterize known or new tissue-specific cell states without a single-cell reference. Starfysh improves the characterization of spatial dynamics in complex tissues using histology images and enables the comparison of niches as spatial hubs across tissues. Integrative analysis of primary estrogen receptor (ER)-positive breast cancer, triple-negative breast cancer (TNBC) and metaplastic breast cancer (MBC) tissues led to the identification of spatial hubs with patient- and disease-specific cell type compositions and revealed metabolic reprogramming shaping immunosuppressive hubs in aggressive MBC.

A large-scale observational study of the causal effects of a behavioral health nudge.

Nudges are interventions promoting healthy behavior without forbidding options or substantial incentives; the Apple Watch, for example, encourages users to stand by delivering a notification if they have been sitting for the first 50 minutes of an hour. On the basis of 76 billion minutes of observational standing data from 160,000 subjects in the public Apple Heart and Movement Study, we estimate the causal effect of this notification using a regression discontinuity design for time series data with time-varying treatment. We show that the nudge increases the probability of standing by up to 43.9% and remains effective with time. The nudge's effectiveness increases with age and is independent of gender. Closing Apple Watch Activity Rings, a visualization of participants' daily progress in Move, Exercise, and Stand, further increases the nudge's impact. This work demonstrates the effectiveness of behavioral health interventions and introduces tools for investigating their causal effect from large-scale observations.

Modeling personalized heart rate response to exercise and environmental factors with wearables data.

Heart rate (HR) response to workout intensity reflects fitness and cardiorespiratory health. Physiological models have been developed to describe such heart rate dynamics and characterize cardiorespiratory fitness. However, these models have been limited to small studies in controlled lab environments and are challenging to apply to noisy-but ubiquitous-data from wearables. We propose a hybrid approach that combines a physiological model with flexible neural network components to learn a personalized, multidimensional representation of fitness. The physiological model describes the evolution of heart rate during exercise using ordinary differential equations (ODEs). ODE parameters are dynamically derived via a neural network connecting personalized representations to external environmental factors, from area topography to weather and instantaneous workout intensity. Our approach efficiently fits the hybrid model to a large set of 270,707 workouts collected from wearables of 7465 users from the Apple Heart and Movement Study. The resulting model produces fitness representations that accurately predict full HR response to exercise intensity in future workouts, with a per-workout median error of 6.1 BPM [4.4-8.8 IQR]. We further demonstrate that the learned representations correlate with traditional metrics of cardiorespiratory fitness, such as VO2 max (explained variance 0.81 ± 0.003). Lastly, we illustrate how our model is naturally interpretable and explicitly describes the effects of environmental factors such as temperature and humidity on heart rate, e.g., high temperatures can increase heart rate by 10%. Combining physiological ODEs with flexible neural networks can yield interpretable, robust, and expressive models for health applications.

Deep generative model deciphers derailed trajectories in acute myeloid leukemia.

Single-cell genomics has the potential to map cell states and their dynamics in an unbiased way in response to perturbations like disease. However, elucidating the cell-state transitions from healthy to disease requires analyzing data from perturbed samples jointly with unperturbed reference samples. Existing methods for integrating and jointly visualizing single-cell datasets from distinct contexts tend to remove key biological differences or do not correctly harmonize shared mechanisms. We present Decipher, a model that combines variational autoencoders with deep exponential families to reconstruct derailed trajectories (https://github.com/azizilab/decipher). Decipher jointly represents normal and perturbed single-cell RNA-seq datasets, revealing shared and disrupted dynamics. It further introduces a novel approach to visualize data, without the need for methods such as UMAP or TSNE. We demonstrate Decipher on data from acute myeloid leukemia patient bone marrow specimens, showing that it successfully characterizes the divergence from normal hematopoiesis and identifies transcriptional programs that become disrupted in each patient when they acquire NPM1 driver mutations.