Biology subjects

Kluger, Y.

Publications and source records attributed to Kluger, Y..

3 recordsLinked to original sources

bioRxiv2018

Zero-preserving imputation of scRNA-seq data using low-rank approximation

Single cell RNA-sequencing (scRNA-seq) methods have revolutionized the study of gene expression but are plagued by dropout events, a phenomenon where genes actually expressed in a given cell are incorrectly measured as unexpressed. We present a method based on low-rank approximation which successfully replaces these dropouts (zero expression levels of unobserved expressed genes) by nonzero values, while preserving biologically non-expressed genes (true biological zeros) at zero expression levels. We validate our approach and compare it to two state-of-the-art methods. We show that it recovers true expression of marker genes while preserving biological zeros, increases separation of known cell types and improves correlation of simulated cells to their true profiles. Furthermore, our method is dramatically more scalable, allowing practitioners to quickly and easily recover expression of even the largest scRNA-seq datasets.

bioinformatics↗

bioRxiv2018

A Highly Efficient and Faithful MDS Patient-Derived Xenotransplantation Model for Pre-Clinical Studies

Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. We developed a novel MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient \"MISTRG\" mice that for the first time provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients' dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample's genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.

cancer biology↗

bioRxiv2016

Methods for detecting co-mutated pathways in cancer samples to inform treatment selection

Tumor genomes evolve through a selection of mutations. These mutations may complement each other to promote tumorigenesis. To better understand the functional interactions of different processes in cancer, we studied mutation data of a set of tumors and identified significantly co-mutated pathways. Fishers exact test is a standard approach that can be used to assess the significance of the joint dysregulation of pathways pairs across a patient population. We developed a robust test to identify co-occurrence using DNA mutations, which overcomes deficiencies of the Fishers exact test by taking into account the large variability in overall mutation load and sequencing depth. Applying our method to a study of six common cancer types, we identify enrichment of co-mutated signal transduction pathways such as IP3 synthesis and PI3K and pairs of co-mutated pathways involving other processes such as immunity and development. We observed enrichment of clonal co-mutation of the proteasome and apoptosis pathways in colorectal cancer, which suggests potential mechanisms for immune evasion.

bioinformatics↗