Biology subjects

Wolf, F. A.

Publications and source records attributed to Wolf, F. A..

9 recordsLinked to original sources

bioRxiv2021

anndata: Annotated data

anndata is a Python package for handling annotated data matrices in memory and on disk (github.com/theislab/anndata), positioned between pandas and xarray. anndata offers a broad range of computationally efficient features including, among others, sparse data support, lazy operations, and a PyTorch interface. Statement of needGenerating insight from high-dimensional data matrices typically works through training models that annotate observations and variables via low-dimensional representations. In exploratory data analysis, this involves iterative training and analysis using original and learned annotations and task-associated representations. anndata offers a canonical data structure for book-keeping these, which is neither addressed by pandas (McKinney, 2010), nor xarray (Hoyer & Hamman, 2017), nor commonly-used modeling packages like scikit-learn (Pedregosa et al., 2011).

bioinformatics↗

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

Learning interpretable latent autoencoder representations with annotations of feature sets

Existing methods for learning latent representations for single-cell RNA-seq data are based on autoencoders and factor models. However, representations learned by autoencoders are hard to interpret and representations learned by factor models have limited flexibility. Here, we introduce a framework for learning interpretable autoencoders based on regularized linear decoders. It decomposes variation into interpretable components using prior knowledge in the form of annotated feature sets obtained from public databases. Through this, it provides an alternative to enrichment techniques and factor models for the task of explaining observed variation with biological knowledge. Benchmarking our model on two single-cell RNA-seq datasets, we demonstrate how our model outperforms an existing factor model regarding scalability while maintaining interpretability.

bioinformatics↗

bioRxiv2019

Generalizing RNA velocity to transient cell states through dynamical modeling

The introduction of RNA velocity in single cells has opened up new ways of studying cellular differentiation. The originally proposed framework obtains velocities as the deviation of the observed ratio of spliced and unspliced mRNA from an inferred steady state. Errors in velocity estimates arise if the central assumptions of a common splicing rate and the observation of the full splicing dynamics with steady-state mRNA levels are violated. With scVelo (https://scvelo.org), we address these restrictions by solving the full transcriptional dynamics of splicing kinetics using a likelihood-based dynamical model. This generalizes RNA velocity to a wide variety of systems comprising transient cell states, which are common in development and in response to perturbations. We infer gene-specific rates of transcription, splicing and degradation, and recover the latent time of the underlying cellular processes. This latent time represents the cells internal clock and is based only on its transcriptional dynamics. Moreover, scVelo allows us to identify regimes of regulatory changes such as stages of cell fate commitment and, therein, systematically detects putative driver genes. We demonstrate that scVelo enables disentangling heterogeneous subpopulation kinetics with unprecedented resolution in hippocampal dentate gyrus neurogenesis and pancreatic endocrinogenesis. We anticipate that scVelo will greatly facilitate the study of lineage decisions, gene regulation, and pathway activity identification.

bioinformatics↗

bioRxiv2018

Generative modeling and latent space arithmetics predict single-cell perturbation response across cell types, studies and species

Accurately modeling cellular response to perturbations is a central goal of computational biology. While such modeling has been proposed based on statistical, mechanistic and machine learning models in specific settings, no generalization of predictions to phenomena absent from training data ( out-of-sample) has yet been demonstrated. Here, we present scGen, a model combining variational autoencoders and latent space vector arithmetics for high-dimensional single-cell gene expression data. In benchmarks across a broad range of examples, we show that scGen accurately models dose and infection response of cells across cell types, studies and species. In particular, we demonstrate that scGen learns cell type and species specific response implying that it captures features that distinguish responding from non-responding genes and cells. With the upcoming availability of large-scale atlases of organs in healthy state, we envision scGen to become a tool for experimental design through in silico screening of perturbation response in the context of disease and drug treatment.

bioinformatics↗

bioRxiv2017

Graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells

Single-cell RNA-seq quantifies biological heterogeneity across both discrete cell types and continuous cell transitions. Partition-based graph abstraction (PAGA) provides an interpretable graph-like map of the arising data manifold, based on estimating connectivity of manifold partitions (https://github.com/theislab/paga). PAGA maps provide interpretable discrete and continuous latent coordinates for both disconnected and continuous structure in data, preserve the global topology of data, allow analyzing data at different resolutions and result in much higher computational efficiency of the typical exploratory data analysis workflow -- one million cells take on the order of a minute, a speedup of 130 times compared to UMAP. We demonstrate the method by inferring structure-rich cell maps with consistent topology across four hematopoietic datasets, confirm the reconstruction of lineage relations of adult planaria and the zebrafish embryo, benchmark computational performance on a neuronal dataset and detect a biological trajectory in one deep-learning processed image dataset.

bioinformatics↗

bioRxiv2017

Scanpy for analysis of large-scale single-cell gene expression data

We present Scanpy, a scalable toolkit for analyzing single-cell gene expression data. It includes preprocessing, visualization, clustering, pseudotime and trajectory inference, differential expression testing and simulation of gene regulatory networks. The Python-based implementation efficiently deals with datasets of more than one million cells and enables easy interfacing of advanced machine learning packages. Code is available from https://github.com/theislab/scanpy.

bioinformatics↗

bioRxiv2016

Model-based branching point detection in single-cell data by K-Branches clustering

MotivationThe identification of heterogeneities in cell populations by utilizing single-cell technologies such as single-cell RNA-Seq, enables inference of cellular development and lineage trees. Several methods have been proposed for such inference from high-dimensional single-cell data. They typically assign each cell to a branch in a differentiation trajectory. However, they commonly assume specific geometries such as tree-like developmental hierarchies and lack statistically sound methods to decide on the number of branching events.\n\nResultsWe present K-Branches, a solution to the above problem by locally fitting half-lines to single-cell data, introducing a clustering algorithm similar to K-Means. These halflines are proxies for branches in the differentiation trajectory of cells. We propose a modified version of the GAP statistic for model selection, in order to decide on the number of lines that best describe the data locally. In this manner, we identify the location and number of subgroups of cells that are associated with branching events and full differentiation, respectively. We evaluate the performance of our method on single-cell RNA-Seq data describing the differentiation of myeloid progenitors during hematopoiesis, single-cell qPCR data of mouse blastocyst development and artificial data.\n\nAvailabilityAn R implementation of K-Branches is freely available at https://github.com/theislab/kbranches\n\nContactfabian.theis@helmholtz-muenchen.de

bioinformatics↗

bioRxiv2016

Deep Learning for Imaging Flow Cytometry: Cell Cycle Analysis of Jurkat Cells

We show that deep convolutional neural networks combined with non-linear dimension reduction enable reconstructing biological processes based on raw image data. We demonstrate this by recon-structing the cell cycle of Jurkat cells and disease progression in diabetic retinopathy. In further analysis of Jurkat cells, we detect and separate a subpopulation of dead cells in an unsupervised manner and, in classifying discrete cell cycle stages, we reach a 6-fold reduction in error rate compared to a recent approach based on boosting on image features. In contrast to previous methods, deep learning based predictions are fast enough for on-the-fly analysis in an imaging flow cytometer.

cell biology↗