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Classification of developmental toxicants in a human iPSC transcriptomics-based test

ABSTRACT: There is a great need for in vitro tests that identify developmental toxicants in relation to human oral doses and blood concentrations. In the present study, we used the hiPSC-based UKK-24h-test and analyzed genome-wide expression profiles of 23 known teratogens and 16 non-teratogens. All compounds were analyzed at the maximal plasma concentration (Cmax) and the 20-fold Cmax for a 24 h incubation period in three independent experiments. Using the 1,000 probe sets with the highest variability and including information on cytotoxicity, a penalized logistic regression based classifier (top-1,000 classifier) reached an AUC, accuracy, sensitivity, and specificity of 0.96, 0.92, 0.96 and 0.88, respectively to correctly classify the compounds as teratogens or non-teratogens. This top-1,000 classifier reached a higher AUC, accuracy and sensitivity than a second classifier (SPS-classifier), which used the number of significant probe sets to classify the compounds. At least, the SPS-classifier had a specificity of 1. Classification at 20-fold Cmax did not lead to better performance metrics than testing at 1-fold Cmax. Finally, inclusion of cytotoxicity information into the classifier clearly improved the performance metrics. In conclusion, although further optimization by additional readouts and inclusion of cell systems that model different developmental processes is required, the UKK-24h-test will support the early discovery-phase detection of human developmental toxicants already in its present form.

ORGANISM(S): Homo sapiens

PROVIDER: GSE187001 | GEO | 2022/06/24

REPOSITORIES: GEO

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Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyteÂ® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyteÂ® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyteÂ® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyteÂ® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyteÂ® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyteÂ® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator

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Classification of developmental toxicants in a human iPSC transcriptomics-based test

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