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Hicks, D.

Publications and source records attributed to Hicks, D..

20 records · Page 2Linked to original sources

Parameter estimation and identifiability in a neural population model for electro-cortical activity

Electroencephalography (EEG) provides a non-invasive measure of brain electrical activity. Neural population models, where large numbers of interacting neurons are considered collectively as a macroscopic system, have long been used to understand features in EEG signals. By tuning dozens of input parameters describing the excitatory and inhibitory neuron populations, these models can reproduce prominent features of the EEG such as the alpha-rhythm. However, the inverse problem, of directly estimating the parameters from fits to EEG data, remains unsolved. Solving this multi-parameter non-linear fitting problem will potentially provide a real-time method for characterizing average neuronal properties in human subjects. Here we perform unbiased fits of a 22-parameter neural population model to EEG data from 82 individuals, using both particle swarm optimization and Markov chain Monte Carlo sampling. We estimate how much is learned about individual parameters by computing Kullback-Leibler divergences between posterior and prior distributions for each parameter. Results indicate that only a single parameter, that determining the dynamics of inhibition, is directly identifiable, while other parameters have large, though correlated, uncertainties. We show that the eigenvalues of the Fisher information matrix are roughly uniformly spaced over a log scale, indicating that the model is sloppy, like many of the regulatory network models in systems biology. These eigenvalues indicate that the system can be modeled with a low effective dimensionality, with inhibition being prominent in driving system behavior.\n\nAuthor summaryElectroencephalography (EEG), where electrodes are used to measure electric potential on the outside of the scalp, provides a simple, non-invasive way to study brain activity. Physiological interpretation of features in EEG signals has often involved use of collective models of neural populations. These neural population models have dozens of input parameters to describe the properties of inhibitory and excitatory neurons. Being able to estimate these parameters by direct fits to EEG data holds the promise of providing a real-time non-invasive method of inferring neuronal properties in different individuals. However, it has long been impossible to fit these nonlinear, multi-parameter models effectively. Here we describe fits of a 22-parameter neural population model to EEG spectra from 82 different subjects, all exhibiting alpha-oscillations. We show how only one parameter, that describing inhibitory dynamics, is constrained by the data, although all parameters are correlated. These results indicate that inhibition plays a central role in the generation and modulation of the alpha-rhythm in humans.

neuroscience↗

Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours

The implementation of personalised medicine in childhood cancers has been limited by a lack of clinically validated multi-target sequencing approaches specific for paediatric solid tumours. In order to support innovative clinical trials in high-risk patients with unmet need, we have developed a clinically relevant targeted sequencing panel spanning 311 kb and comprising 78 genes involved in childhood cancers. A total of 132 samples were used for the validation of the panel, including Horizon Discovery cell blends (n=4), cell lines (n=15), formalin-fixed paraffin embedded (FFPE, n=83) and fresh frozen tissue (FF, n=30) patient samples. Cell blends containing known single nucleotide variants (SNVs, n=528) and small insertion-deletions (indels n=108) were used to define panel sensitivities of [≥]98% for SNVs and [≥]83% for indels [95% CI] and panel specificity of [≥]98% [95% CI] for SNVs. FFPE samples performed comparably to FF samples (n=15 paired). Of 95 well-characterised genetic abnormalities in 33 clinical specimens and 13 cell lines (including SNVs, indels, amplifications, rearrangements and chromosome losses), 94 (98.9%) were detected by our approach. We have validated a robust and practical methodology to guide clinical management of children with solid tumours based on their molecular profiles. Our work demonstrates the value of targeted gene sequencing in the development of precision medicine strategies in paediatric oncology.

genomics↗