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Workflow for defining reference chemicals for assessing performance of in vitro assays.

ABSTRACT: Instilling confidence in use of in vitro assays for predictive toxicology requires evaluation of assay performance. Performance is typically assessed using reference chemicals--compounds with defined activity against the test system target. However, developing reference chemical lists has historically been very resource-intensive. We developed a semi-automated process for selecting and annotating reference chemicals across many targets in a standardized format and demonstrate the workflow here. A series of required fields defines the potential reference chemical: the in vitro molecular target, pathway, or phenotype affected; and the chemical's mode (e.g. agonist, antagonist, inhibitor). Activity information was computationally extracted into a database from multiple public sources including non-curated scientific literature and curated chemical-biological databases, resulting in the identification of chemical activity in 2995 biological targets. Sample data from literature sources covering 54 molecular targets ranging from data-poor to data-rich was manually checked for accuracy. Precision rates were 82.7% from curated data sources and 39.5% from automated literature extraction. We applied the final reference chemical lists to evaluating performance of EPA's ToxCast program in vitro bioassays. The level of support, i.e. the number of independent reports in the database linking a chemical to a target, was found to strongly correlate with likelihood of positive results in the ToxCast assays, although individual assay performance had considerable variation. This overall approach allows rapid development of candidate reference chemical lists for a wide variety of targets that can facilitate performance evaluation of in vitro assays as a critical step in imparting confidence in alternative approaches.

SUBMITTER: Judson RS

PROVIDER: S-EPMC6784312 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Workflow for defining reference chemicals for assessing performance of in vitro assays.

Judson Richard S RS Thomas Russell S RS Baker Nancy N Simha Anita A Howey Xia Meng XM Marable Carmen C Kleinstreuer Nicole C NC Houck Keith A KA

ALTEX 20181217 2

Instilling confidence in use of in vitro assays for predictive toxicology requires evaluation of assay performance. Performance is typically assessed using reference chemicals--compounds with defined activity against the test system target. However, developing reference chemical lists has historically been very resource-intensive. We developed a semi-automated process for selecting and annotating reference chemicals across many targets in a standardized format and demonstrate the workflow here. ...[more]

PMID: 30570668

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Project description:BackgroundThe Short Physical Performance Battery (SPPB) is an established test of physical performance. We provide reference values for SPPB and determine SPPB performance and cut-offs in assessing sarcopenia for Asian community-dwelling older adults.MethodsFive hundred thirty-eight (57.8% women) community-dwelling adults aged 21-90 years were recruited. SPPB and its subtest scores and timings (8 ft. gait speed (GS), five-times repeated chair sit-to-stand (STS) and balance) were determined. Appendicular lean mass divided by height-squared, muscle strength (handgrip) and physical performance (6 m GS, STS and SPPB) were assessed to define sarcopenia for various Asian criteria. Area under the ROC curve (AUC) was used to assess performance of SPPB and subtests in discriminating sarcopenia in adults aged ≥60 years. Optimal SPPB and GS subtest cut-offs for each sarcopenia criterion were determined by maximizing sensitivity and specificity.ResultsThe mean SPPB score was 11.6(SD 1.1) in men and 11.5(SD1.2) in women. Majority of participants(≥50%) aged 21-80 years achieved the maximum SPPB score. SPPB total and subtest scores generally decreased with age (all p < 0.001), but did not differ between sex. Among older adults (≥60 years), SPPB and GS subtest had varied performance in assessing sarcopenia (AUC 0.54-0.64 and 0.51-0.72, respectively), and moderate-to-excellent performance in assessing severe sarcopenia (AUC 0.69-0.98 and 0.75-0.95, respectively), depending on sarcopenia definitions. The optimal cut-offs for discriminating sarcopenia in both sexes were SPPB ≤11points and GS subtest ≤1.0 m/s. The most common optimal cut-offs for discriminating severe sarcopenia according to various definitions were SPPB ≤11points in both sexes, and GS ≤0.9 m/s in men and ≤ 1.0 m/s in women.ConclusionsPopulation-specific normative SPPB values are important for use in diagnostic criteria and to interpret results of studies evaluating and establishing appropriate treatment goals. Performance on the SPPB should be reported in terms of the total sum score and registered time to complete the repeated-chair STS and 8-ft walk tests. The performance of GS subtest was comparable to SPPB and could be a useful, simple and accessible screening tool for discriminating severe sarcopenia in community-dwelling older adults.

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Workflow for defining reference chemicals for assessing performance of in vitro assays.

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Workflow for defining reference chemicals for assessing performance of in vitro assays.

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