Publications

Selected Publications

(*equal contribution; _lab members; †corresponding)

Microbial colonization programs are structured by breastfeeding and guide healthy respiratory development

Liat Shenhav†*, Kelsey Fehr, Myrtha E. Reyna, Charisse Petersen,Darlene L. Y. Dai, Ruixue Dai, Vanessa Breton,Laura Rossi, Marek Smieja, Elinor Simons,Michael A. Silverman, Maayan Levy,Lars Bode, Catherine J. Field, Jean S Marshall,Theo J. Moraes, Piush J. Mandhane, Stuart E. Turvey,Padmaja Subbarao, Michael G. Surette,Meghan B. Azad. Cell (2024)

Breastfeeding and microbial colonization during infancy occur within a critical time window for development, and both are thought to influence the risk of respiratory illness. However, the mechanisms underlying the protective effects of breastfeeding and the regulation of microbial colonization are poorly understood. Here, we profiled the nasal and gut microbiomes, breastfeeding characteristics, and maternal milk composition of 2,227 children from the CHILD Cohort Study. We identified robust colonization patterns that, together with milk components, predict preschool asthma and mediate the protective effects of breastfeeding. We found that early cessation of breastfeeding (before 3 months)leads to the premature acquisition of microbial species and functions, including Ruminococcus gnavus and tryptophan biosynthesis, which were previously linked to immune modulation and asthma. Conversely, longer exclusive breastfeeding supports a paced microbial development, protecting against asthma. These findings underscore the importance of extended breastfeeding for respiratory health and highlight potential microbial targets for intervention.

Contamination source modeling with SCRuB improves cancer phenotype prediction from microbiome data

George I. Austin, Heekuk Park, Yoli Meydan, Tanya Sezin, Yue Clare Lou, Brian A. Firek, Michael J. Morowitz, Jillian F. Banfield, Angela M. Christiano, Itsik Pe’er, Anne-Catrin Uhlemann, Liat Shenhav†*, Tal Korem. Nature Biotechnology. PMID: 36928429 (2023)

Short Summary: Sequencing-based approaches for the analysis of microbial communities are susceptible to contamination, which could mask biological signals or generate artifactual ones. Methods for in silico decontamination using controls are routinely used, but do not make optimal use of information shared across samples and cannot handle taxa that only partially originate in contamination or leakage of biological material into controls.

Context-aware dimensionality reduction deconvolutes gut microbial community dynamics

Cameron Martino, Liat Shenhav*, George Armstrong, Daniel McDonald, Yoshiki Vázquez-Baeza, James T Morton, Lingjing Jiang, Austin D Swafford, Eran Halperin, Rob Knight. Nature Biotechnology. PMCID: PMC7878194 (2021)

Short Summary: The translational power of human microbiome studies is limited by high interindividual variation. We describe a dimensionality reduction tool, compositional tensor factorization (CTF), that incorporates information from the same host across multiple samples to reveal patterns driving differences in microbial composition across phenotypes. CTF identifies robust patterns in sparse compositional datasets, allowing for the detection of microbial changes associated with specific phenotypes that are reproducible across datasets.

Resource conservation manifests in the genetic code

Liat Shenhav*, David Zeevi. Science. PMID: 33154134 (2020)

Short Summary: Nutrient limitation drives competition for resources across organisms. However, much is unknown about how selective pressures resulting from nutrient limitation shape microbial coding sequences. Here, we study this “resource-driven selection” by using metagenomic and single-cell data of marine microbes, alongside environmental measurements.

FEAST: fast expectation-maximization for microbial source tracking

Liat Shenhav, Mike Thompson, Tyler A Joseph, Leah Briscoe, Ori Furman, David Bogumil, Itzhak Mizrahi, Itsik Pe’er, Eran Halperin. Nature Methods, 2019. PMCID: PMC8535041 (2019)

Short Summary: A major challenge of analyzing the compositional structure of microbiome data is identifying its potential origins. Here, we introduce fast expectation-maximization microbial source tracking (FEAST), a ready-to-use scalable framework that can simultaneously estimate the contribution of thousands of potential source environments in a timely manner, thereby helping unravel the origins of complex microbial communities

Publications

2024

Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer’s disease

Annalise Schweickart, Richa Batra, Bryan J Neth, Cameron Martino, Liat Shenhav, Anru R Zhang, Pixu Shi, Naama Karu, Kevin Huynh, Peter J Meikle, Leyla Schimmel, Amanda Hazel Dilmore, Kaj Blennow, Henrik Zetterberg, Colette Blach, Pieter C Dorrestein, Rob Knight, Suzanne Craft, Rima Kaddurah-Daouk, Jan Krumsiek. npj Metabolic Health and Disease (2024)

Short Summary: Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment.

A conserved interdomain microbial network underpins cadaver decomposition despite environmental variables

Zachary M Burcham, Aeriel D Belk, Bridget B McGivern, Amina Bouslimani, Parsa Ghadermazi, Cameron Martino, Liat Shenhav, Anru R Zhang, Pixu Shi, Alexandra Emmons, Heather L Deel, Zhenjiang Zech Xu, Victoria Nieciecki, Qiyun Zhu, Michael Shaffer, Morgan Panitchpakdi, Kelly C Weldon, Kalen Cantrell, Asa Ben-Hur, Sasha C Reed, Greg C Humphry, Gail Ackermann, Daniel McDonald, Siu Hung Joshua Chan, Melissa Connor, Derek Boyd, Jake Smith, Jenna MS Watson, Giovanna Vidoli, Dawnie Steadman, Aaron M Lynne, Sibyl Bucheli, Pieter C Dorrestein, Kelly C Wrighton, David O Carter, Rob Knight, Jessica L Metcalf. Nature Microbiology, 1-19 (2024)

Short Summary: Microbial breakdown of organic matter is one of the most important processes on Earth, yet the controls of decomposition are poorly understood. Here we track 36 terrestrial human cadavers in three locations and show that a phylogenetically distinct, interdomain microbial network assembles during decomposition despite selection effects of location, climate and season.

Personalized mood prediction from patterns of behavior collected with smartphones

Brunilda Balliu, Chris Douglas, Darsol Seok, Liat Shenhav, Yue Wu, Doxa Chatzopoulou, William Kaiser, Victor Chen, Jennifer Kim, Sandeep Deverasetty, Inna Arnaudova, Robert Gibbons, Eliza Congdon, Michelle G Craske, Nelson Freimer, Eran Halperin, Sriram Sankararaman, Jonathan Flint. npj Digital Medicine 7 (1), 49 (2024)

Short Summary: Over the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer depressive mood. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data.

2023

Microdiversity of the vaginal microbiome is associated with preterm birth

Jingqiu Liao, Liat Shenhav*, Julia A Urban, Myrna Serrano, Bin Zhu, Gregory A Buck, Tal Korem. Nature Communications 14 (1), 4997 (2023)

Short Summary: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The vaginal microbiome has been associated with PTB, yet the mechanisms underlying this association are not fully understood. Understanding microbial genetic adaptations to selective pressures, especially those related to the host, may yield insights into these associations.

Time-Informed Dimensionality Reduction for Longitudinal Microbiome Studies

Pixu Shi, Cameron Martino, Rungang Han, Stefan Janssen, Gregory Buck, Myrna Serrano, Kouros Owzar, Rob Knight, Liat Shenhav†, Anru R Zhang. bioRxiv, 2023.07. 26.550749 (2023)

Short Summary: Complex dynamics of microbial communities underlie their essential roles in health and disease, but our understanding of these dynamics remains incomplete. To bridge this gap, longitudinal microbiome data are being rapidly generated, yet their power is limited by technical challenges in design and analysis, such as varying temporal sampling, complex correlation structures over feature and time, and high dimensionality.

DVT-Net: A Multimodal Deep Vascular Topology Network for Disease Prediction

Ye Tian, Geoffrey Wu, Srilaxmi Bearelly, Andrew Laine, Kaveri A Thakoor, Liat Shenhav†. 2023 IEEE 20th International Symposium on Biomedical Imaging (ISBI), 1-5 (2023)

Short Summary: Blood vessel networks deliver nutrients, and remove waste, to maintain tissue homeostasis. Disease complications can alter vascular network morphology, which may disrupt tissue functioning. Many systemic and ocular diseases are associated with altered vessel morphology, including diabetic retinopathy (DR), glaucoma, occlusion, hypertension, and Alzheimer’s disease, suggesting their detection may have a diagnostic value. Currently, microvascular diseases are assessed by visual inspection of retinal images.

Quantifying replicability and consistency in systematic reviews

Iman Jaljuli, Yoav Benjamini, Liat Shenhav, Orestis A Panagiotou, Ruth Heller. Statistics in Biopharmaceutical Research 15 (2), 372-385 (2023)

Short Summary: Systematic reviews and meta-analyses are important tools for synthesizing evidence from multiple studies. They serve to increase power and improve precision, in the same way that large studies can do, but also to establish the consistency of effects and replicability of results across studies. In this work we propose statistical tools to quantify replicability of effect signs (or directions) and their consistency.

2022

Using community ecology theory and computational microbiome methods to study human milk as a biological system

Liat Shenhav†*, Meghan B Azad. Msystems 7 (1), e01132-21 (2022)

Short Summary: Human milk is a complex and dynamic biological system that has evolved to optimally nourish and protect human infants. Yet, according to a recent priority-setting review, “our current understanding of human milk composition and its individual components and their functions fails to fully recognize the importance of the chronobiology and systems biology of human milk in the context of milk synthesis, optimal timing and duration of feeding, and period of lactation.

STENSL: Microbial Source Tracking with ENvironment SeLection

Ulzee An, Liat Shenhav†, Christine A Olson, Elaine Y Hsiao, Eran Halperin, Sriram Sankararaman. Msystems 7 (5), e00995-21 (2022)

Shorty Summary: Microbial source tracking analysis has emerged as a widespread technique for characterizing the properties of complex microbial communities. However, this analysis is currently limited to source environments sampled in a specific study. In order to expand the scope beyond one single study and allow the exploration of source environments using large databases and repositories, such as the Earth Microbiome Project, a source selection procedure is required.

Compositionally aware phylogenetic beta-diversity measures better resolve microbiomes associated with phenotype

Cameron Martino, Daniel McDonald, Kalen Cantrell, Amanda Hazel Dilmore, Yoshiki Vázquez-Baeza, Liat Shenhav, Justin P Shaffer, Gibraan Rahman, George Armstrong, Celeste Allaband, Se Jin Song, Rob Knight. Msystems 7 (3), e00050-22 (2022)

Short Summary: Microbiome data have several specific characteristics (sparsity and compositionality) that introduce challenges in data analysis. The integration of prior information regarding the data structure, such as phylogenetic structure and repeated-measure study designs, into analysis, is an effective approach for revealing robust patterns in microbiome data.

2021

Context-aware dimensionality reduction deconvolutes gut microbial community dynamics

Cameron Martino, Liat Shenhav*, Clarisse A Marotz, George Armstrong, Daniel McDonald, Yoshiki Vázquez-Baeza, James T Morton, Lingjing Jiang, Maria Gloria Dominguez-Bello, Austin D Swafford, Eran Halperin, Rob Knight

Short Summary: The translational power of human microbiome studies is limited by high interindividual variation. We describe a dimensionality reduction tool, compositional tensor factorization (CTF), that incorporates information from the same host across multiple samples to reveal patterns driving differences in microbial composition across phenotypes. CTF identifies robust patterns in sparse compositional datasets, allowing for the detection of microbial changes associated with specific phenotypes that are reproducible across datasets.

The Discriminatory Power of Vocal Features in Detecting Mental Illnesses Under Complex Context

Wei Pan, Liat Shenhav, Amber Afshan, Abeer Alwan, Jonathan Flint, Tianli Liu, Bin Hu, Tingshao Zhu. Researchsquare (2021)

Short Summary: Vocal features have been proposed as a way to identify depression by distinguishing depression from healthy controls, but while there have been some claims for success, the degree to which changes in vocal features are specific to depression has not been systematically studied. In particular, it is not clear whether vocal features are characteristic of mental ill health in general, rather than characteristic of different psychiatric diagnoses.

Naturalization of the microbiota developmental trajectory of Cesarean-born neonates after vaginal seeding

Se Jin Song, Jincheng Wang, Cameron Martino, Lingjing Jiang, Wesley K Thompson, Liat Shenhav, Daniel McDonald, Clarisse Marotz, Paul R Harris, Caroll D Hernandez, Nora Henderson, Elizabeth Ackley, Deanna Nardella, Charles Gillihan, Valentina Montacuti, William Schweizer, Melanie Jay, Joan Combellick, Haipeng Sun, Izaskun Garcia-Mantrana, Fernando Gil Raga, Maria Carmen Collado, Juana I Rivera-Viñas, Maribel Campos-Rivera, Jean F Ruiz-Calderon, Rob Knight, Maria Gloria Dominguez-Bello. Med 2 (8), 951-964. e5 (2021)

Short Summary: Early microbiota perturbations are associated with disorders that involve immunological underpinnings. Cesarean section (CS)-born babies show altered microbiota development in relation to babies born vaginally. Here we present the first statistically powered longitudinal study to determine the effect of restoring exposure to maternal vaginal fluids after CS birth.

2020

Spatiotemporal Modeling of Microbial Communities

Liat Shenhav. University of California, Los Angeles (2020)

Short Summary: Microbial communities can undergo rapid changes, that can both cause and indicate host disease, rendering longitudinal microbiome studies key for understanding microbiome-associated disorders. However, most standard statistical methods, based on random samples, are not applicable for addressing the methodological and statistical challenges associated with repeated, structured observations of a complex ecosystem.

Stochasticity constrained by deterministic effects of diet and age drive rumen microbiome assembly dynamics

Ori Furman, Liat Shenhav, Goor Sasson, Fotini Kokou, Hen Honig, Shamay Jacoby, Tomer Hertz, Otto X Cordero, Eran Halperin, Itzhak Mizrahi. Nature communications 11 (1), 1904 (2020)

Short Summary: How complex communities assemble through the animal’s life, and how predictable the process is remains unexplored. Here, we investigate the forces that drive the assembly of rumen microbiomes throughout a cow’s life, with emphasis on the balance between stochastic and deterministic processes. We analyse the development of the rumen microbiome from birth to adulthood using 16S-rRNA amplicon sequencing data and find that the animals shared a group of core successional species that invaded early on and persisted until adulthood.

Compositional Lotka-Volterra describes microbial dynamics in the simplex

Tyler A Joseph, Liat Shenhav, Joao B Xavier, Eran Halperin, Itsik Pe’er. PLoS computational biology 16 (5), e1007917 (2020)

Short Summary: Dynamic changes in microbial communities play an important role in human health and disease. Specifically, deciphering how microbial species in a community interact with each other and their environment can elucidate mechanisms of disease, a problem typically investigated using tools from community ecology. Yet, such methods require measurements of absolute densities, whereas typical datasets only provide estimates of relative abundances.

2019

Re-examining the robustness of voice features in predicting depression: Compared with baseline of confounders

Wei Pan, Jonathan Flint, Liat Shenhav, Tianli Liu, Mingming Liu, Bin Hu, Tingshao Zhu. PloS one 14 (6), e0218172 (2019)

Short Summary: A large proportion of Depression Disorder patients do not receive an effective diagnosis, which makes it necessary to find a more objective assessment to facilitate a more rapid and accurate diagnosis of depression. Speech data is easy to acquire clinically, its association with depression has been studied, although the actual predictive effect of voice features has not been examined.

Modeling the temporal dynamics of the gut microbial community in adults and infants

Liat Shenhav, Ori Furman, Leah Briscoe, Mike Thompson, Justin D Silverman, Itzhak Mizrahi, Eran Halperin. PLoS computational biology 15 (6), e1006960 (2019)

Short Summary: Given the highly dynamic and complex nature of the human gut microbial community, the ability to identify and predict time-dependent compositional patterns of microbes is crucial to our understanding of the structure and functions of this ecosystem. One factor that could affect such time-dependent patterns is microbial interactions, wherein community composition at a given time point affects the microbial composition at a later time point. However, the field has not yet settled on the degree of this effect. Specifically, it has been recently suggested that only a minority of taxa depend on the microbial composition in earlier times.

2018

Using stochastic approximation techniques to efficiently construct confidence intervals for heritability

R Schweiger, E Fisher, E Rahmani, L Shenhav, S Rosset, E Halperin. Journal of Computational Biology 25 (7), 794-808 (2018)

Short Summary: Estimation of heritability is an important task in genetics. The use of linear mixed models (LMMs) to determine narrow-sense single-nucleotide polymorphism (SNP)-heritability and related quantities has received much recent attention, due of its ability to account for variants with small effect sizes. Typically, heritability estimation under LMMs uses the restricted maximum likelihood (REML) approach.

Statistical considerations in the design and analysis of longitudinal microbiome studies

JD Silverman, L Shenhav, E Halperin, S Mukherjee, LA David. BioRxiv, 448332 (2018)

Short Summary: Longitudinal studies of microbial communities have emphasized that host-associated microbiota are highly dynamic as well as underscoring the potential biomedical relevance of understanding these dynamics. Despite this increasing appreciation, statistical challenges in the design and analysis of longitudinal microbiome studies such as sequence counting, technical variation, signal aliasing, contamination, sparsity, missing data, and algorithmic scalability remain.

BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference

Elior Rahmani, Regev Schweiger, Liat Shenhav, Theodora Wingert, Ira Hofer, Eilon Gabel, Eleazar Eskin, Eran Halperin. Genome biology 19, 1-18 (2018)

Short Summary: We introduce a Bayesian semi-supervised method for estimating cell counts from DNA methylation by leveraging an easily obtainable prior knowledge on the cell-type composition distribution of the studied tissue. We show mathematically and empirically that alternative methods which attempt to infer cell counts without methylation reference only capture linear combinations of cell counts rather than provide one component per cell type.

2017

Genome-wide methylation data mirror ancestry information

Elior Rahmani, Liat Shenhav, Regev Schweiger, Paul Yousefi, Karen Huen, Brenda Eskenazi, Celeste Eng, Scott Huntsman, Donglei Hu, Joshua Galanter, Sam S Oh, Melanie Waldenberger, Konstantin Strauch, Harald Grallert, Thomas Meitinger, Christian Gieger, Nina Holland, Esteban G Burchard, Noah Zaitlen, Eran Halperin. Epigenetics & chromatin 10, 1-12 (2017)

Short Summary: The translational power of human microbiome studies is limited by high interindividual variation. We describe a dimensionality reduction tool, compositional tensor factorization (CTF), that incorporates information from the same host across multiple samples to reveal patterns driving differences in microbial composition across phenotypes. CTF identifies robust patterns in sparse compositional datasets, allowing for the detection of microbial changes associated with specific phenotypes that are reproducible across datasets.

GLINT: a user-friendly toolset for the analysis of high-throughput DNA-methylation array data

Elior Rahmani, Reut Yedidim, Liat Shenhav, Regev Schweiger, Omer Weissbrod, Noah Zaitlen, Eran Halperin. Bioinformatics 33 (12), 1870-1872 (2017)

Short Summary: GLINT is a user-friendly command-line toolset for fast analysis of genome-wide DNA methylation data generated using the Illumina human methylation arrays. GLINT, which does not require any programming proficiency, allows an easy execution of Epigenome-Wide Association Study analysis pipeline under different models while accounting for known confounders in methylation data.

A Bayesian framework for estimating cell type composition from DNA methylation without the need for methylation reference

Elior Rahmani, Regev Schweiger, Liat Shenhav, Eleazar Eskin, Eran Halperin. Research in Computational Molecular Biology: 21st Annual International Conference, RECOMB 2017, Hong Kong, China, May 3-7, 2017, Proceedings 21 (2017)

Short Summary: Genome-wide DNA methylation levels measured from a target tissue across a population have become ubiquitous over the last few years, as methylation status is suggested to hold great potential for better understanding the role of epigenetics. Different cell types are known to have different methylation profiles.

2016

Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis

Zohar Meiri, Shay Keren, Amir Rosenblatt, Tal Sarig, Liat Shenhav, David Varssano. Cornea 35 (3), 417-428 (2016)

Short Summary: A systemic literature review and meta-analysis of ocular functional and structural parameters of patients with KCN undergoing cross-linking procedures were performed using PubMed and the web of science. A literature search was performed for relevant peer-reviewed publications on population-based studies. Data were analyzed with R software (Meta library), and heterogeneity was assessed with the Cochran Q and I 2. A random-effects model was used for high heterogeneity; otherwise a fixed model was used.

2015

Quantifying replicability in systematic reviews: the r-value

Liat Shenhav, Ruth Heller, Yoav Benjamini. arXiv preprint arXiv:1502.00088 (2015)

Short Summary: In order to assess the effect of a health care intervention, it is useful to look at an ensemble of relevant studies. The Cochrane Collaboration's admirable goal is to provide systematic reviews of all relevant clinical studies, in order to establish whether or not there is a conclusive evidence about a specific intervention. This is done mainly by conducting a meta-analysis: a statistical synthesis of results from a series of systematically collected studies.