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Measurement and models accounting for cell death capture hidden variation in compound response.

ABSTRACT: Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have divergent effects on the tumor microenvironment, immune response, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug-response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, additive compound pairs with distinct growth/death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.

SUBMITTER: Bae SY

PROVIDER: S-EPMC7171175 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Measurement and models accounting for cell death capture hidden variation in compound response.

Bae Song Yi SY Guan Ning N Yan Rui R Warner Katrina K Taylor Scott D SD Meyer Aaron S AS

Cell death & disease 20200420 4

Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have divergent effects on the tumor microenvironment, immune response, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound ...[more]

PMID: 32312951

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Project description:BackgroundStudies of animal movement using location data are often faced with two challenges. First, time series of animal locations are likely to arise from multiple behavioral states (e.g., directed movement, resting) that cannot be observed directly. Second, location data can be affected by measurement error, including failed location fixes. Simultaneously addressing both problems in a single statistical model is analytically and computationally challenging. To both separate behavioral states and account for measurement error, we used a two-stage modeling approach to identify resting locations of fishers (Pekania pennanti) based on GPS and accelerometer data.MethodsWe developed a two-stage modelling approach to estimate when and where GPS-collared fishers were resting for 21 separate collar deployments on 9 individuals in southern Oregon. For each deployment, we first fit independent hidden Markov models (HMMs) to the time series of accelerometer-derived activity measurements and apparent step lengths to identify periods of movement and resting. Treating the state assignments as given, we next fit a set of linear Gaussian state space models (SSMs) to estimate the location of each resting event.ResultsParameter estimates were similar across collar deployments. The HMMs successfully identified periods of resting and movement with posterior state assignment probabilities greater than 0.95 for 97% of all observations. On average, fishers were in the resting state 63% of the time. Rest events averaged 5 h (4.3 SD) and occurred most often at night. The SSMs allowed us to estimate the 95% credible ellipses with a median area of 0.12 ha for 3772 unique rest events. We identified 1176 geographically distinct rest locations; 13% of locations were used on > 1 occasion and 5% were used by > 1 fisher. Females and males traveled an average of 6.7 (3.5 SD) and 7.7 (6.8 SD) km/day, respectively.ConclusionsWe demonstrated that if auxiliary data are available (e.g., accelerometer data), a two-stage approach can successfully resolve both problems of latent behavioral states and GPS measurement error. Our relatively simple two-stage method is repeatable, computationally efficient, and yields directly interpretable estimates of resting site locations that can be used to guide conservation decisions.

Dataset Information

Measurement and models accounting for cell death capture hidden variation in compound response.

Publications

Measurement and models accounting for cell death capture hidden variation in compound response.

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