Dataset Information

Discounting and Augmentation in Causal Conditional Reasoning: Causal Models or Shallow Encoding?

ABSTRACT: Recent research comparing mental models theory and causal Bayes nets for their ability to account for discounting and augmentation inferences in causal conditional reasoning had some limitations. One of the experiments used an ordinal scale and multiple items and analysed the data by subjects and items. This procedure can create a variety of problems that can be resolved by using an appropriate cumulative link function mixed models approach in which items are treated as random effects. Experiment 1 replicated this earlier experiment and analysed the results using appropriate data analytic techniques. Although successfully replicating earlier research, the pattern of results could be explained by a much simpler "shallow encoding" hypothesis. Experiment 2 introduced a manipulation to critically test this hypothesis. The results favoured the causal Bayes nets predictions and not shallow encoding and were not consistent with mental models theory. Experiment 1 provided qualified support for the causal Bayes net approach using appropriate statistics because it also replicated the failure to observe one of the predicted main effects. Experiment 2 discounted one plausible explanation for this failure. While within the limited goals that were set for these experiments they were successful, more research is required to account for the pattern of findings using this paradigm.

SUBMITTER: Hall S

PROVIDER: S-EPMC5193512 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Discounting and Augmentation in Causal Conditional Reasoning: Causal Models or Shallow Encoding?

Hall Simon S Ali Nilufa N Chater Nick N Oaksford Mike M

PloS one 20161228 12

Recent research comparing mental models theory and causal Bayes nets for their ability to account for discounting and augmentation inferences in causal conditional reasoning had some limitations. One of the experiments used an ordinal scale and multiple items and analysed the data by subjects and items. This procedure can create a variety of problems that can be resolved by using an appropriate cumulative link function mixed models approach in which items are treated as random effects. Experimen ...[more]

PMID: 28030583

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Project description:Drug-induced cardiac toxicity has been implicated in 31% of drug withdrawals in the USA. The fact that the risk for cardiac-related adverse events goes undetected in preclinical studies for so many drugs underscores the need for better, more predictive in vitro safety screens to be deployed early in the drug discovery process. Unfortunately, many questions remain about the ability to accurately translate findings from simple cellular systems to the mechanisms that drive toxicity in the complex in vivo environment. In this study, we analyzed translatability of cardiotoxic effects for a diverse set of drugs from rodents to two different cell systems (rat heart tissue-derived cells (H9C2) and primary rat cardiomyocytes (RCM)) based on their transcriptional response. To unravel the altered pathway, we applied a novel computational systems biology approach, the Causal Reasoning Engine (CRE), to infer upstream molecular events causing the observed gene expression changes. By cross-referencing the cardiotoxicity annotations with the pathway analysis, we found evidence of mechanistic convergence towards common molecular mechanisms regardless of the cardiotoxic phenotype. We also experimentally verified two specific molecular hypotheses that translated well from in vivo to in vitro (Kruppel-like factor 4, KLF4 and Transforming growth factor beta 1, TGFB1) supporting the validity of the predictions of the computational pathway analysis. In conclusion, this work demonstrates the use of a novel systems biology approach to predict mechanisms of toxicity such as KLF4 and TGFB1 that translate from in vivo to in vitro. We also show that more complex in vitro models such as primary rat cardiomyocytes may not offer any advantage over simpler models such as immortalized H9C2 cells in terms of translatability to in vivo effects if we consider the right endpoints for the model. Further assessment and validation of the generated molecular hypotheses would greatly enhance our ability to design predictive in vitro cardiotoxicity assays.

Dataset Information

Discounting and Augmentation in Causal Conditional Reasoning: Causal Models or Shallow Encoding?

Publications

Discounting and Augmentation in Causal Conditional Reasoning: Causal Models or Shallow Encoding?

Similar Datasets

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