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Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework.

ABSTRACT: The JAK-STAT pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational workflow to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to IL-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified select cytokine-induced gene sets associated with late pSTAT3 timeframes and a preferential pSTAT1 reduction upon JAK2 inhibition. We predicted and validated the impact of JAK2 inhibition on gene expression, identifying dynamically regulated genes that were sensitive or insensitive to JAK2 variation. Thus, we successfully linked STAT signaling dynamics to gene expression to support future efforts targeting pathology-associated STAT-driven gene sets. This serves as a first step in developing multi-level prediction models to understand and perturb gene expression outputs from signaling systems.

SUBMITTER: Cheemalavagu N

PROVIDER: S-EPMC10245690 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework.

Cheemalavagu Neha N Shoger Karsen E KE Cao Yuqi M YM Michalides Brandon A BA Botta Samuel A SA Faeder James R JR Gottschalk Rachel A RA

bioRxiv : the preprint server for biology 20230520

The JAK-STAT pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational workflow to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to IL-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-m ...[more]

PMID: 37292918

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Project description:BackgroundMaternal morbidity and mortality remain critical health concerns globally. As a result, reducing the maternal mortality ratio (MMR) is part of goal 3 in the global sustainable development goals (SDGs), and previously, it was an important indicator in the Millennium Development Goals (MDGs). Therefore, identifying high-risk groups during pregnancy is crucial for decision-makers and medical practitioners to mitigate mortality and morbidity. However, the availability of accurate predictive models for maternal mortality and maternal health risks is challenging. Compared with traditional predictive models, machine learning algorithms have emerged as promising predictive modelling methods providing accurate predictive models.MethodsThis work aims to explore the potential of machine learning (ML) algorithms in maternal risk level prediction using a nationwide maternal mortality dataset from Oman for the first time. A total of 402 maternal deaths from 1991 to 2023 in Oman were included in this study. We utilised principal component analysis (PCA) in the ML algorithms and compared them to the results of model performance without PCA. We employed and compared ten ML algorithms, including decision tree (DT), random forest (RF), K-Nearest Neighbors (KNN), Naïve Bayes (NB), Extreme Gradient Boosting (xgboost), Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Logistic Regression (LR), Support Vector Machine (SVM) and Artificial Neural Network (ANN). Different metrics, including, accuracy, sensitivity, precision, and the F1- score, were utilised to assess Model performance.ResultsThe results indicated that the RF model outperformed the other methods in predicting the risk level (low or high) with an accuracy of 75.2%, precision of 85.7% and F1- score of 73% after PCA was applied.ConclusionsWe applied several machine learning models to predict maternal risk levels for the first time using real data from Oman. RF outperformed the other algorithms in this classification problem. A reliable estimate of maternal risk level would facilitate intervention plans for medical practitioners to reduce maternal death.

Dataset Information

Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework.

Publications

Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework.

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