Biology subjects

Lopez-Paz, D.

Publications and source records attributed to Lopez-Paz, D..

3 recordsLinked to original sources

bioRxiv2021

Compositional perturbation autoencoder for single-cell response modeling

Recent advances in multiplexed single-cell transcriptomics experiments are facilitating the high-throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible, so computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep-learning approaches for single-cell response modeling. CPA encodes and learns transcriptional drug responses across different cell type, dose, and drug combinations. The model produces easy-to-interpret embeddings for drugs and cell types, which enables drug similarity analysis and predictions for unseen dosage and drug combinations. We show that CPA accurately models single-cell perturbations across compounds, doses, species, and time. We further demonstrate that CPA predicts combinatorial genetic interactions of several types, implying that it captures features that distinguish different interaction programs. Finally, we demonstrate that CPA can generate in-silico 5,329 missing genetic combination perturbations (97.6% of all possibilities) with diverse genetic interactions. We envision our model will facilitate efficient experimental design and hypothesis generation by enabling in-silico response prediction at the single-cell level, and thus accelerate therapeutic applications using single-cell technologies.

bioinformatics↗

bioRxiv2020

Discriminating the Influence of Correlated Factors from Multivariate Observations: the Back-to-Back Regression

Identifying causes solely from observations can be particularly challenging when i) potential factors are difficult to manipulate independently and ii) observations are multi-dimensional. To address this issue, we introduce "Back-to-Back" regression (B2B), a linear method designed to efficiently measure, from a set of correlated factors, those that most plausibly account for multidimensional observations. First, we prove the consistency of B2B, its links to other linear approaches, and show how it provides a robust, unbiased and interpretable scalar estimate for each factor. Second, we use a variety of simulated data to show that B2B outperforms least-squares regression and cross-decomposition techniques (e.g. canonical correlation analysis and partial least squares) on causal identification when the factors and the observations are partially collinear. Finally, we apply B2B to magneto-encephalography of 102 subjects recorded during a reading task to test whether our method appropriately disentangles the respective contribution of word length and word frequency - two correlated factors known to cause early and late brain responses respectively. The results show that these two factors are better disentangled with B2B than with other standard techniques.

neuroscience↗

bioRxiv2019

Poincare Maps for Analyzing Complex Hierarchies in Single-Cell Data

The need to understand cell developmental processes spawned a plethora of computational methods for discovering hierarchies from scRNAseq data. However, existing techniques are based on Euclidean geometry, a suboptimal choice for modeling complex cell trajectories with multiple branches. To overcome this fundamental representation issue we propose Poincare maps, a method that harness the power of hyperbolic geometry into the realm of single-cell data analysis. Often understood as a continuous extension of trees, hyperbolic geometry enables the embedding of complex hierarchical data in only two dimensions while preserving the pairwise distances between points in the hierarchy. This enables direct exploratory analysis and the use of our embeddings in a wide variety of downstream data analysis tasks, such as visualization, clustering, lineage detection and pseudo-time inference. When compared to existing methods --unable to address all these important tasks using a single embedding-- Poincare maps produce state-of-the-art two-dimensional representations of cell trajectories on multiple scRNAseq datasets. More specifically, we demonstrate that Poincare maps allow in a straightforward manner to formulate new hypotheses about biological processes unbeknown to prior methods. Significance statementThe discovery of hierarchies in biological processes is central to developmental biology. We propose Poincare maps, a new method based on hyperbolic geometry to discover continuous hierarchies from pairwise similarities. We demonstrate the efficacy of our method on multiple single-cell datasets on tasks such as visualization, clustering, lineage identification, and pseudo-time inference.

bioinformatics↗