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Structural Equation Modeling of In silico Perturbations.

ABSTRACT: Gene expression is controlled by multiple regulators and their interactions. Data from genome-wide gene expression assays can be used to estimate molecular activities of regulators within a model organism and extrapolate them to biological processes in humans. This approach is valuable in studies to better understand complex human biological systems which may be involved in diseases and hence, have potential clinical relevance. In order to achieve this, it is necessary to infer gene interactions that are not directly observed (i.e. latent or hidden) by way of structural equation modeling (SEM) on the expression levels or activities of the downstream targets of regulator genes. Here we developed an R Shiny application, termed "Structural Equation Modeling of In silico Perturbations (SEMIPs)" to compute a two-sided t-statistic (T-score) from analysis of gene expression data, as a surrogate to gene activity in a given human specimen. SEMIPs can be used in either correlational studies between outcome variables of interest or subsequent model fitting on multiple variables. This application implements a 3-node SEM model that consists of two upstream regulators as input variables and one downstream reporter as an outcome variable to examine the significance of interactions among these variables. SEMIPs enables scientists to investigate gene interactions among three variables through computational and mathematical modeling (i.e. in silico). In a case study using SEMIPs, we have shown that putative direct downstream genes of the GATA Binding Protein 2 (GATA2) transcription factor are sufficient to infer its activities in silico for the conserved progesterone receptor (PGR)-GATA2-SRY-box transcription factor 17 (SOX17) genetic network in the human uterine endometrium.

SUBMITTER: Li J

PROVIDER: S-EPMC8652139 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Firearm homicides disproportionately affect Black communities. Redlining - discriminatory lending practices of the early 20th century - are associated with current increased rates of firearm violence. Poverty and concentrated disadvantage are also associated with firearm violence. The interaction of these factors with racist redlining housing practices remains unclear. We used generalized structural equation modeling to characterize the mediators through which redlining practices of the 1930s led to present rates of firearm violence in Boston using a negative binomial model. Principle component analysis was used to create four distinct mediating variables representing census block socioeconomic and built environment information, while reducing dimensionality. We calculated the direct effect between harmful (Red and Yellow) vs beneficial (Green) designations and firearm incident rate, indirect effect between redlining designation and firearm incident rate through each mediating variable, and the total effect. The percentage mediation of each mediator was subsequently calculated. Red and Yellow areas of Boston were associated with an 11•1 (95% CI 5•5,22•4) and 11•4 (5•7,22•8) increased incident rate of shooting when compared to Green. In the pathway between Red designation and firearm incident rate, poverty and poor educational attainment mediated 20% of the interaction, share of rented housing mediated 8%, and Black share of the population 3%. In the pathway between Yellow designation and firearm incident rate, poverty and poor educational attainment mediated 16% of the association, and Black share of the population mediated 13%. Redlining practices of the 1930s potentially contribute to increased rates of firearm violence through changes to neighborhood environments, namely through preclusion from homeownership, poverty, poor educational attainment, and concentration (i.e. segregation) of Black communities. These downstream mediating factors serve as points for policy interventions to address urban firearm violence. Michael Poulson and Miriam Neufeld were supported by T32 Training Grants (HP10028, GM86308).

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Structural Equation Modeling of In silico Perturbations.

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