Integration of gene expression and DNA methylation data across different experiments.

Integrative analysis of multi-omic datasets has proven to be extremely valuable in cancer research and precision medicine. However, obtaining multimodal data from the same samples is often difficult. Integrating multiple datasets of different omics remains a challenge, with only a few available algorithms developed to solve it. Here, we present INTEND (IntegratioN of Transcriptomic and EpigeNomic Data), a novel algorithm for integrating gene expression and DNA methylation datasets covering disjoint sets of samples. To enable integration, INTEND learns a predictive model between the two omics by training on multi-omic data measured on the same set of samples. In comprehensive testing on 11 TCGA (The Cancer Genome Atlas) cancer datasets spanning 4329 patients, INTEND achieves significantly superior results compared with four state-of-the-art integration algorithms. We also demonstrate INTEND's ability to uncover connections between DNA methylation and the regulation of gene expression in the joint analysis of two lung adenocarcinoma single-omic datasets from different sources. INTEND's data-driven approach makes it a valuable multi-omic data integration tool. The code for INTEND is available at https://github.com/Shamir-Lab/INTEND.

MONET: Multi-omic module discovery by omic selection.

Recent advances in experimental biology allow creation of datasets where several genome-wide data types (called omics) are measured per sample. Integrative analysis of multi-omic datasets in general, and clustering of samples in such datasets specifically, can improve our understanding of biological processes and discover different disease subtypes. In this work we present MONET (Multi Omic clustering by Non-Exhaustive Types), which presents a unique approach to multi-omic clustering. MONET discovers modules of similar samples, such that each module is allowed to have a clustering structure for only a subset of the omics. This approach differs from most existent multi-omic clustering algorithms, which assume a common structure across all omics, and from several recent algorithms that model distinct cluster structures. We tested MONET extensively on simulated data, on an image dataset, and on ten multi-omic cancer datasets from TCGA. Our analysis shows that MONET compares favorably with other multi-omic clustering methods. We demonstrate MONET's biological and clinical relevance by analyzing its results for Ovarian Serous Cystadenocarcinoma. We also show that MONET is robust to missing data, can cluster genes in multi-omic dataset, and reveal modules of cell types in single-cell multi-omic data. Our work shows that MONET is a valuable tool that can provide complementary results to those provided by existent algorithms for multi-omic analysis.

NEMO: cancer subtyping by integration of partial multi-omic data.

MOTIVATION: Cancer subtypes were usually defined based on molecular characterization of single omic data. Increasingly, measurements of multiple omic profiles for the same cohort are available. Defining cancer subtypes using multi-omic data may improve our understanding of cancer, and suggest more precise treatment for patients. RESULTS: We present NEMO (NEighborhood based Multi-Omics clustering), a novel algorithm for multi-omics clustering. Importantly, NEMO can be applied to partial datasets in which some patients have data for only a subset of the omics, without performing data imputation. In extensive testing on ten cancer datasets spanning 3168 patients, NEMO achieved results comparable to the best of nine state-of-the-art multi-omics clustering algorithms on full data and showed an improvement on partial data. On some of the partial data tests, PVC, a multi-view algorithm, performed better, but it is limited to two omics and to positive partial data. Finally, we demonstrate the advantage of NEMO in detailed analysis of partial data of AML patients. NEMO is fast and much simpler than existing multi-omics clustering algorithms, and avoids iterative optimization. AVAILABILITY AND IMPLEMENTATION: Code for NEMO and for reproducing all NEMO results in this paper is in github: https://github.com/Shamir-Lab/NEMO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Inaccuracy of the log-rank approximation in cancer data analysis.

The log-rank test statistic is very broadly used in biology. Unfortunately, P-values based on the popular chi-square approximation are often inaccurate and can be misleading.

Multi-omic and multi-view clustering algorithms: review and cancer benchmark.

Recent high throughput experimental methods have been used to collect large biomedical omics datasets. Clustering of single omic datasets has proven invaluable for biological and medical research. The decreasing cost and development of additional high throughput methods now enable measurement of multi-omic data. Clustering multi-omic data has the potential to reveal further systems-level insights, but raises computational and biological challenges. Here, we review algorithms for multi-omics clustering, and discuss key issues in applying these algorithms. Our review covers methods developed specifically for omic data as well as generic multi-view methods developed in the machine learning community for joint clustering of multiple data types. In addition, using cancer data from TCGA, we perform an extensive benchmark spanning ten different cancer types, providing the first systematic comparison of leading multi-omics and multi-view clustering algorithms. The results highlight key issues regarding the use of single- versus multi-omics, the choice of clustering strategy, the power of generic multi-view methods and the use of approximated p-values for gauging solution quality. Due to the growing use of multi-omics data, we expect these issues to be important for future progress in the field.

Plasma proteomics in the UK Biobank reveals youthful brains and immune systems promote healthspan and longevity.

Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer's disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements. Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation.

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk 1 . Brain aging is complex and accompanied by many cellular changes 2-20 . However, the influence that aged cells have on neighboring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in aging tissues have not yet been developed. Here, we generate spatiotemporal data at single-cell resolution for the mouse brain across lifespan, and we develop the first machine learning models based on spatial transcriptomics ('spatial aging clocks') to reveal cell proximity effects during brain aging and rejuvenation. We collect a single-cell spatial transcriptomics brain atlas of 4.2 million cells from 20 distinct ages and across two rejuvenating interventions-exercise and partial reprogramming. We identify spatial and cell type-specific transcriptomic fingerprints of aging, rejuvenation, and disease, including for rare cell types. Using spatial aging clocks and deep learning models, we find that T cells, which infiltrate the brain with age, have a striking pro-aging proximity effect on neighboring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating effect on neighboring cells. By developing computational tools to identify mediators of these proximity effects, we find that pro-aging T cells trigger a local inflammatory response likely via interferon-γ whereas pro-rejuvenating neural stem cells impact the metabolism of neighboring cells possibly via growth factors (e.g. vascular endothelial growth factor) and extracellular vesicles, and we experimentally validate some of these predictions. These results suggest that rare cells can have a drastic influence on their neighbors and could be targeted to counter tissue aging. We anticipate that these spatial aging clocks will not only allow scalable assessment of the efficacy of interventions for aging and disease but also represent a new tool for studying cell-cell interactions in many spatial contexts.

Single cell Hi-C identifies plastic chromosome conformations underlying the gastrulation enhancer landscape.

Embryonic development involves massive proliferation and differentiation of cell lineages. This must be supported by chromosome replication and epigenetic reprogramming, but how proliferation and cell fate acquisition are balanced in this process is not well understood. Here we use single cell Hi-C to map chromosomal conformations in post-gastrulation mouse embryo cells and study their distributions and correlations with matching embryonic transcriptional atlases. We find that embryonic chromosomes show a remarkably strong cell cycle signature. Despite that, replication timing, chromosome compartment structure, topological associated domains (TADs) and promoter-enhancer contacts are shown to be variable between distinct epigenetic states. About 10% of the nuclei are identified as primitive erythrocytes, showing exceptionally compact and organized compartment structure. The remaining cells are broadly associated with ectoderm and mesoderm identities, showing only mild differentiation of TADs and compartment structures, but more specific localized contacts in hundreds of ectoderm and mesoderm promoter-enhancer pairs. The data suggest that while fully committed embryonic lineages can rapidly acquire specific chromosomal conformations, most embryonic cells are showing plastic signatures driven by complex and intermixed enhancer landscapes.

Spontaneous Changes in Ploidy Are Common in Yeast.

Changes in ploidy are relatively rare, but play important roles in the development of cancer and the acquisition of long-term adaptations. Genome duplications occur across the tree of life, and can alter the rate of adaptive evolution. Moreover, by allowing the subsequent loss of individual chromosomes and the accumulation of mutations, changes in ploidy can promote genomic instability and/or adaptation. Although many studies have been published in the last years about changes in chromosome number and their evolutionary consequences, tracking and measuring the rate of whole-genome duplications have been extremely challenging. We have systematically studied the appearance of diploid cells among haploid yeast cultures evolving for over 100 generations in different media. We find that spontaneous diploidization is a relatively common event, which is usually selected against, but under certain stressful conditions may become advantageous. Furthermore, we were able to detect and distinguish between two different mechanisms of diploidization, one that requires whole-genome duplication (endoreduplication) and a second that involves mating-type switching despite the use of heterothallic strains. Our results have important implications for our understanding of evolution and adaptation in fungal pathogens and the development of cancer, and for the use of yeast cells in biotechnological applications.