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Hierarchical modeling and simulation to optimize cell village experimental design and the analysis of scRNA-seq data

Award Number: F31HG013890
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Hierarchical modeling and simulation to optimize cell village experimental design and the analysis of scRNA-seq data - PROJECT SUMMARY Elucidating the genetic and environmental drivers of disease is critical to precision medicine. Advancements in in vitro human stem cell culture are accelerating disease and therapeutic research across individuals of di- verse genetic backgrounds. Cell villages are an e!cient platform, that pools populations of 10-100 genetically distinct, human stem cell lines, to study how genetic variation and environment inﬂuence a spectrum of molec- ular phenotypes. This experimental design allows researchers to apply selection and perturbation treatments to large, ancestrally diverse cell populations, while simultaneously measuring phenotype di↵erences between donors through molecular and omics assays. While villages show a lot of promise for uncovering Gene x Environment (GxE) interactions and the end e↵ect on disease, two main limitations need to be addressed: (i) experimental methods need to be reﬁned to ensure reproducibility and adequate statistical power and (ii) statistical analysis tools need to be built to incorporate the full structure of these data. We aim to address these limitations by ﬁrst developing standards for cell village experimental design through statistical modeling and simulation of village donor growth. Speciﬁcally, we will test how di↵erent experimental parameters a↵ect the amount of variation in donor growth rate estimates, the consistency of these predictions and whether experiments can maintain donor representation over the desired time frames. These factors will be important as we want to help researchers design experiments that minimize the variance in the growth rate estimates, while maintaining high genetic diversity throughout the entire experiment. Using this experimentally validated simulation framework, we will build a user- friendly tool that enables researchers to input their own preliminary data to project how di↵erent experimental design choices might impact the signals they are able to detect in the data and if donors might drop out or take over the population. In the second aim, we will build a hierarchical model of single cell RNA-seq (scRNA-seq) time series count data. The scRNA-seq pipeline will focus on two main applications: (i) a statistical tool that addresses the sparsity in single cell time series count data while accounting for natural variation in villages, and (ii) a tool that estimates the sequencing depth and village design needed to optimize statistical power. This work will help researchers conduct reproducible, high powered cell village experiments while fully leveraging the structure of the data. Improving cell village experimental and statistical methods will give researchers a powerful platform for investigating individual disease risk and potential for speciﬁc therapeutic interventions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $41,872 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	001	2	12/15/2025	NON-COMPETING CONTINUATION	$41,872
2026	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	000	1	12/12/2025	NEW	$0
														Subtotal = $41,872

Issue Date FY: 2024 ( Subtotal = $41,308 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Human Genome Research	000	1	9/24/2024	NEW	$41,308
														Subtotal = $41,308

Grand Total All Awards = $83,180

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Hierarchical modeling and simulation to optimize cell village experimental design and the analysis of scRNA-seq data

Award Number: F31HG013890

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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