RESUMO
Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. The results reveal a wider range of developmental programs than previously characterized. Cells gradually adopt either a terminal stromal state or a mesenchymal-to-epithelial transition state. The latter gives rise to populations related to pluripotent, extra-embryonic, and neural cells, with each harboring multiple finer subpopulations. The analysis predicts transcription factors and paracrine signals that affect fates and experiments validate that the TF Obox6 and the cytokine GDF9 enhance reprogramming efficiency. Our approach sheds light on the process and outcome of reprogramming and provides a framework applicable to diverse temporal processes in biology.
Assuntos
Reprogramação Celular/genética , Perfilação da Expressão Gênica/métodos , Análise de Célula Única/métodos , Animais , Diferenciação Celular/genética , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Fibroblastos/metabolismo , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Análise de Sequência de RNA/métodos , Fatores de Transcrição/metabolismoRESUMO
Determinantal point processes (DPPs) have recently become popular tools for modeling the phenomenon of negative dependence, or repulsion, in data. However, our understanding of an analogue of a classical parametric statistical theory is rather limited for this class of models. In this work, we investigate a parametric family of Gaussian DPPs with a clearly interpretable effect of parametric modulation on the observed points. We show that parameter modulation impacts the observed points by introducing directionality in their repulsion structure, and the principal directions correspond to the directions of maximal (i.e., the most long-ranged) dependency. This model readily yields a viable alternative to principal component analysis (PCA) as a dimension reduction tool that favors directions along which the data are most spread out. This methodological contribution is complemented by a statistical analysis of a spiked model similar to that employed for covariance matrices as a framework to study PCA. These theoretical investigations unveil intriguing questions for further examination in random matrix theory, stochastic geometry, and related topics.
RESUMO
High-dimensional statistical tests often ignore correlations to gain simplicity and stability leading to null distributions that depend on functionals of correlation matrices such as their Frobenius norm and other â r norms. Motivated by the computation of critical values of such tests, we investigate the difficulty of estimation the functionals of sparse correlation matrices. Specifically, we show that simple plug-in procedures based on thresholded estimators of correlation matrices are sparsity-adaptive and minimax optimal over a large class of correlation matrices. Akin to previous results on functional estimation, the minimax rates exhibit an elbow phenomenon. Our results are further illustrated in simulated data as well as an empirical study of data arising in financial econometrics.
RESUMO
Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug development, disease diagnosis, and risk prediction. However, the low throughput of LC-MS poses a major challenge for biomarker discovery, annotation, and experimental comparison, necessitating the merging of multiple datasets. Current data pooling methods encounter practical limitations due to their vulnerability to data variations and hyperparameter dependence. Here, we introduce GromovMatcher, a flexible and user-friendly algorithm that automatically combines LC-MS datasets using optimal transport. By capitalizing on feature intensity correlation structures, GromovMatcher delivers superior alignment accuracy and robustness compared to existing approaches. This algorithm scales to thousands of features requiring minimal hyperparameter tuning. Manually curated datasets for validating alignment algorithms are limited in the field of untargeted metabolomics, and hence we develop a dataset split procedure to generate pairs of validation datasets to test the alignments produced by GromovMatcher and other methods. Applying our method to experimental patient studies of liver and pancreatic cancer, we discover shared metabolic features related to patient alcohol intake, demonstrating how GromovMatcher facilitates the search for biomarkers associated with lifestyle risk factors linked to several cancer types.