Similar Datasets
Project description:One challenge of cancer precision medicine is the heterogeneity of genetic and non-genetic alterations that result in dysfunctional molecular pathways. As an emerging drug discovery effort, dysregulation in Hippo pathway signaling is known to drive oncogenesis across numerous cancer types but lacks recurrent mutation(s) that are often found in other canonical signaling pathways. Here, we use first principles approach to develop a machine-learning framework to identify a robust, lineage-independent gene expression signature to quantify Hippo pathway dependency in cancers. Through integrating data from multi-omics platforms, this data-driven approach has enabled identifying a proposed combination with MAPK inhibition for direct targeting of Hippo pathway dependent cancers for which we then elucidate the underlying molecular mechanism. The results underscore how a multifaceted approach, computational models combined with laboratory efforts, can accelerate precision medicine efforts toward co-targeting Hippo and MAPK pathways, an approach that can be generalized to other key cancer signaling pathways to define therapeutic strategies.
2021-01-26 | GSE161010 | GEO
Project description:One challenge of cancer precision medicine is the heterogeneity of genetic and non-genetic alterations that result in dysfunctional molecular pathways. As an emerging drug discovery effort, dysregulation in Hippo pathway signaling is known to drive oncogenesis across numerous cancer types but lacks recurrent mutation(s) that are often found in other canonical signaling pathways. Here, we use first principles approach to develop a machine-learning framework to identify a robust, lineage-independent gene expression signature to quantify Hippo pathway dependency in cancers. Through integrating data from multi-omics platforms, this data-driven approach has enabled identifying a proposed combination with MAPK inhibition for direct targeting of Hippo pathway dependent cancers for which we then elucidate the underlying molecular mechanism. The results underscore how a multifaceted approach, computational models combined with laboratory efforts, can accelerate precision medicine efforts toward co-targeting Hippo and MAPK pathways, an approach that can be generalized to other key cancer signaling pathways to define therapeutic strategies.
2021-01-26 | GSE161018 | GEO
Project description:A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency
| PRJNA675152 | ENA
Project description:A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (ATAC-seq)
| PRJNA675182 | ENA
Project description:A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (RNA-seq)
| PRJNA675107 | ENA
Project description:BackgroundRetinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP.MethodsBy mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa.ResultsA mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARα1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa.ConclusionsThe possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.
| S-EPMC10848380 | biostudies-literature
Project description:IntroductionThe study objective was to build a machine learning model to predict incident mild cognitive impairment, Alzheimer's Disease, and related dementias from structured data using administrative and electronic health record sources.MethodsA cohort of patients (n = 121,907) and controls (n = 5,307,045) was created for modeling using data within 2 years of patient's incident diagnosis date. Additional cohorts 3-8 years removed from index data are used for prediction. Training cohorts were matched on age, gender, index year, and utilization, and fit with a gradient boosting machine, lightGBM.ResultsIncident 2-year model quality on a held-out test set had a sensitivity of 47% and area-under-the-curve of 87%. In the 3-year model, the learned labels achieved 24% (71%), which dropped to 15% (72%) in year 8.DiscussionThe ability of the model to discriminate incident cases of dementia implies that it can be a worthwhile tool to screen patients for trial recruitment and patient management.
| S-EPMC6920083 | biostudies-literature
Project description:BackgroundOxidative stress produced a large amount of reactive oxygen species (ROS), which played a pivotal role in balanced ability and determining cell fate. The activated Nrf2 signaling pathway that responds to the excessive ROS regulated the expressions of antiapoptotic proteins, antioxidative enzymes, drug transporters, and detoxifying factors.MethodsThe Nrf2 signaling pathway-related genes that had a direct relationship with Nrf2, including ATF4, BACH1, CREBBP, CUL3, EIF2AK3, EP300, FOS, FOSL1, GSK3B, JUN, KEAP1, MAF, MAFF, MAFG, MAFK, MAPK1, MAPK3, MAPK7, MAPK8, MAPK9, PIK3CA, PRRT2, and RIT1, were selected to do a systematic pan-cancer analysis. The relationship of Nrf2 signaling pathway-related gene expressions with tumor mutation burden, microsatellite status, clinical characteristics, immune system, cancer stemness index, and drug sensitivity was calculated by the Spearson correlation analysis across 11,057 subjects representing 33 cancer types. The prognosis models in lung squamous carcinoma, breast cancer, and stomach cancer were constructed with the Cox multivariate regression analysis and least absolute shrinkage and selection operator (Lasso) regression.ResultsMany Nrf2 signaling pathway-related genes were differently expressed between tumor and normal tissues. PIK3CA showed high mutation rate in pan-cancer. The expressions of Nrf2 signaling pathway-related genes were significantly related to tumor mutation burden, copy number variant, microsatellite instability score, survival rate, pathological stage, immune phenotype, immune score, immune cell, cancer stemness index, and drug sensitivity. The prognosis models were significantly associated with survival rate in lung squamous carcinoma, breast cancer, and stomach cancer; and the prognosis model-based riskscore was significantly associated with clinicopathological characteristics of each cancer.ConclusionsThe study provided a comprehensive pan-cancer landscape of Nrf2 pathway-related genes. Based on the same Nrf2 pathway-related genes, the different prognosis models were constructed for different types of cancers.
| S-EPMC8886747 | biostudies-literature
Project description:Machine learning (ML) is largely used to develop automatic predictors in migraine classification but automatic predictors for medication overuse (MO) in migraine are still in their infancy. Thus, to understand the benefits of ML in MO prediction, we explored an automated predictor to estimate MO risk in migraine. To achieve this objective, a study was designed to analyze the performance of a customized ML-based decision support system that combines support vector machines and Random Optimization (RO-MO). We used RO-MO to extract prognostic information from demographic, clinical and biochemical data. Using a dataset of 777 consecutive migraine patients we derived a set of predictors with discriminatory power for MO higher than that observed for baseline SVM. The best four were incorporated into the final RO-MO decision support system and risk evaluation on a five-level stratification was performed. ROC analysis resulted in a c-statistic of 0.83 with a sensitivity and specificity of 0.69 and 0.87, respectively, and an accuracy of 0.87 when MO was predicted by at least three RO-MO models. Logistic regression analysis confirmed that the derived RO-MO system could effectively predict MO with ORs of 5.7 and 21.0 for patients classified as probably (3 predictors positive), or definitely at risk of MO (4 predictors positive), respectively. In conclusion, a combination of ML and RO - taking into consideration clinical/biochemical features, drug exposure and lifestyle - might represent a valuable approach to MO prediction in migraine and holds the potential for improving model precision through weighting the relative importance of attributes.
| S-EPMC7327028 | biostudies-literature
Project description:Drug resistance threatens the effective prevention and treatment of an ever-increasing range of human infections. This highlights an urgent need for new and improved drugs with novel mechanisms of action to avoid cross-resistance. Current cell-based drug screens are, however, restricted to binary live/dead readouts with no provision for mechanism of action prediction. Machine learning methods are increasingly being used to improve information extraction from imaging data. These methods, however, work poorly with heterogeneous cellular phenotypes and generally require time-consuming human-led training. We have developed a semi-supervised machine learning approach, combining human- and machine-labeled training data from mixed human malaria parasite cultures. Designed for high-throughput and high-resolution screening, our semi-supervised approach is robust to natural parasite morphological heterogeneity and correctly orders parasite developmental stages. Our approach also reproducibly detects and clusters drug-induced morphological outliers by mechanism of action, demonstrating the potential power of machine learning for accelerating cell-based drug discovery.
| S-EPMC7518791 | biostudies-literature