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Heskes, T.

Publications and source records attributed to Heskes, T..

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Hierarchical Bayesian inference for concurrent model fitting and comparison for group studies

Computational modeling plays an important role in modern neuroscience research. Much previous research has relied on statistical methods, separately, to address two problems that are actually interdependent. First, given a particular computational model, Bayesian hierarchical techniques have been used to estimate individual variation in parameters over a population of subjects, leveraging their population-level distributions. Second, candidate models are themselves compared, and individual variation in the expressed model estimated, according to the fits of the models to each subject. The interdependence between these two problems arises because the relevant population for estimating parameters of a model depends on which other subjects express the model. Here, we propose a hierarchical Bayesian inference (HBI) framework for concurrent model comparison, parameter estimation and inference at the population level, combining previous approaches. We show that this framework has important advantages for both parameter estimation and model comparison theoretically and experimentally. The parameters estimated by the HBI show smaller errors compared to other methods. Model comparison by HBI is robust against outliers and is not biased towards overly simplistic models. Furthermore, the fully Bayesian approach of HBI enables researchers to quantify uncertainty in group parameter estimates, for each candidate model separately, and to perform statistical tests on parameters of a population.

neuroscience

Additive Dose Response Models: Explicit Formulations and the Loewe Additivity Consistency Condition

High-throughput techniques allow for massive screening of drug combinations. To find combinations that exhibit an interaction effect, one filters for promising compound combinations by comparing to a response without interaction. A common principle for no interaction is Loewe Additivity which is based on the assumption that no compound interacts with itself and that doses of both compounds for a given effect are equivalent. For the model to be consistent, the doses of both compounds have to be proportional. We call this restriction the Loewe Additivity Consistency Condition (LACC). We derive explicit and implicit null reference models from the Loewe Additivity principle that are equivalent when the LACC holds. Of these two formulations, the implicit formulation is the known General Isobole Equation [1], whereas the explicit one is the novel contribution. The LACC is violated in a significant number of cases. In this scenario the models make different predictions. We analyze two data sets of drug screening that are non-interactive [2, 3] and show that the LACC is mostly violated and Loewe Additivity not defined. Further, we compare the measurements of the non-interactive cases of both data sets to the theoretical null reference models in terms of bias and mean squared error. We demonstrate that the explicit formulation of the null reference model leads to smaller mean squared errors than the implicit one and is much faster to compute.

pharmacology and toxicology