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Predicting Human Clinical Outcomes Using Mouse Multi-Organ Transcriptome.

ABSTRACT: Approximately 90% of pre-clinically validated drugs fail in clinical trials owing to unanticipated clinical outcomes, costing over several hundred million US dollars per drug. Despite such critical importance, translating pre-clinical data to clinical outcomes remain a major challenge. Herein, we designed a modality-independent and unbiased approach to predict clinical outcomes of drugs. The approach exploits their multi-organ transcriptome patterns induced in mice and a unique mouse-transcriptome database "humanized" by machine learning algorithms and human clinical outcome datasets. The cross-validation with small-molecule, antibody, and peptide drugs shows effective and efficient identification of the previously known outcomes of 5,519 adverse events and 11,312 therapeutic indications. In addition, the approach is adaptable to deducing potential molecular mechanisms underlying these outcomes. Furthermore, the approach identifies previously unsuspected repositioning targets. These results, together with the fact that it requires no prior structural or mechanistic information of drugs, illustrate its versatile applications to drug development process.

SUBMITTER: Kozawa S

PROVIDER: S-EPMC7033637 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesFor optimal utilization of healthcare resources, there is a critical need for early identification of COVID-19 patients at risk of poor prognosis as defined by the need for intensive unit care and mechanical ventilation. We tested the feasibility of chest X-ray (CXR)-based radiomics metrics to develop machine-learning algorithms for predicting patients with poor outcomes.MethodsIn this Institutional Review Board (IRB) approved, Health Insurance Portability and Accountability Act (HIPAA) compliant, retrospective study, we evaluated CXRs performed around the time of admission from 167 COVID-19 patients. Of the 167 patients, 68 (40.72%) required intensive care during their stay, 45 (26.95%) required intubation, and 25 (14.97%) died. Lung opacities were manually segmented using ITK-SNAP (open-source software). CaPTk (open-source software) was used to perform 2D radiomics analysis.ResultsOf all the algorithms considered, the AdaBoost classifier performed the best with AUC = 0.72 to predict the need for intubation, AUC = 0.71 to predict death, and AUC = 0.61 to predict the need for admission to the intensive care unit (ICU). AdaBoost had similar performance with ElasticNet in predicting the need for admission to ICU. Analysis of the key radiomic metrics that drive model prediction and performance showed the importance of first-order texture metrics compared to other radiomics panel metrics. Using a Venn-diagram analysis, two first-order texture metrics and one second-order texture metric that consistently played an important role in driving model performance in all three outcome predictions were identified.ConclusionsConsidering the quantitative nature and reliability of radiomic metrics, they can be used prospectively as prognostic markers to individualize treatment plans for COVID-19 patients and also assist with healthcare resource management.Advances in knowledgeWe report on the performance of CXR-based imaging metrics extracted from RT-PCR positive COVID-19 patients at admission to develop machine-learning algorithms for predicting the need for ICU, the need for intubation, and mortality, respectively.

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Predicting Human Clinical Outcomes Using Mouse Multi-Organ Transcriptome.

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