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Parameter Estimation in Systems Biology

Modelling Transcriptional Regulation with Gaussian Processes

author: Neil Lawrence, University of Manchester

Description

Modelling the dynamics of transcriptional processes in the cell requires the knowledge of a number of key biological quantities. While some of them are relatively easy to measure, such as mRNA decay rates and mRNA abundance levels, it is still very hard to measure the active concentration levels of the transcription factor proteins that drive the process and the sensitivity of target genes to these concentrations. In this paper we show how these quantities for a given transcription factor can be inferred from gene expression levels of a set of known target genes. We treat the protein concentration as a latent function with a Gaussian process prior, and include the sensitivities, mRNA decay rates and baseline expression levels as hyperparameters. We apply this procedure to a human leukemia dataset, focusing on the tumour repressor p53 and obtaining results in good accordance with recent biological studies.

Joint work with Guido Sanguinetti and Magnus Rattray.

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Slides
0:01 Modelling Transcriptional Regulation with Gaussian Processes
0:32 Outline
1:02 Online Resources
1:09 Framework
2:47 This Talk
3:33 Linear Response Solution
4:26 Gaussian Processes
5:19 Gaussian Processes
5:54 Covariance Functions
6:32 Covariance Functions
7:04 Covariance Functions
7:08 Covariance Functions
7:27 Different Covariance Functions
7:30 Covariance Samples
7:46 Covariance Samples
7:50 Prior to Posterior
8:00 Gaussian Process Regression
8:05 Gaussian Process Regression
8:17 Gaussian Process Regression
8:25 Covariance of Latent Function
8:31 Computation of Joint Covariance
9:16 Induced Covariance
9:26 Covariance for Transcription Model
10:08 Joint Sampling of x (t) and f (t)
10:40 Joint Sampling of x (t) and f (t)
10:42 Joint Sampling of x (t) and f (t)
10:58 Noise Corruption
11:57 Artificial Data
13:16 Artificial Data Results
14:28 Results
14:35 Linear response analysis
14:39 Linear Response Results
15:25 Results — Transcription Rates
15:35 Results — Transcription Rates
15:38 Results — Transcription Rates
15:56 Linear Response Discussion
16:25 Non-linear Response Model
16:34 Formalism
16:58 Response Results
17:30 Non-linear response analysis
17:47 exp (·) Response Results
18:01 log (1 + exp (f )) Response Results
18:18 3/(1+exp(−f)) Response Results
18:44 Discussion
19:30 Future Directions

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