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"Lawrence, Neil D"
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The atomic human : understanding ourselves in the age of AI
Fears of AI not only concern how it invades our digital lives, but also the implied threat of an intelligence that displaces us from our position at the centre of the world. Neil D. Lawrence's book shows why these fears may be misplaced. Atomism, proposed by Democritus, suggested it was impossible to continue dividing matter down into ever smaller components: eventually we reach a point where a cut cannot be made (the Greek for uncuttable is 'atom'). In the same way, by slicing away at the facets of human intelligence that can be replaced by machines, AI uncovers what is left: an indivisible core that is the essence of humanity. By contrasting our own (evolved, locked-in, embodied) intelligence with the capabilities of machine intelligence through history, the book reveals the technical origins, capabilities and limitations of AI systems, and how they should be wielded.
Book
Accelerating AI for science: open data science for science
Aspirations for artificial intelligence (AI) as a catalyst for scientific discovery are growing. High-profile successes deploying AI in domains such as protein folding have highlighted AI’s potential to unlock new frontiers of scientific knowledge. However, the pathway from AI innovation to deployment in research is not linear. Those seeking to drive a new wave of scientific progress through the application of AI require a diffusion engine that can enhance AI adoption across disciplines. Lessons from previous waves of technology change, experiences of deploying AI in real-world contexts and an emerging research agenda from the AI for science community suggest a framework for accelerating AI adoption. This framework requires action to build supply chains of ideas between disciplines; rapidly transfer technological capabilities through open research; create AI tools that empower researchers; and embed effective data stewardship. Together, these interventions can cultivate an environment of open data science that deliver the benefits of AI across the sciences.
Journal Article
Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays
Genes with similar transcriptional activation kinetics can display very different temporal mRNA profiles because of differences in transcription time, degradation rate, and RNA-processing kinetics. Recent studies have shown that a splicing-associated RNA production delay can be significant. To investigate this issue more generally, it is useful to develop methods applicable to genome-wide datasets. We introduce a joint model of transcriptional activation and mRNA accumulation that can be used for inference of transcription rate, RNA production delay, and degradation rate given data from high-throughput sequencing time course experiments. We combine a mechanistic differential equation model with a nonparametric statistical modeling approach allowing us to capture a broad range of activation kinetics, and we use Bayesian parameter estimation to quantify the uncertainty in estimates of the kinetic parameters. We apply the model to data from estrogen receptor α activation in the MCF-7 breast cancer cell line. We use RNA polymerase II ChIP-Seq time course data to characterize transcriptional activation and mRNA-Seq time course data to quantify mature transcripts. We find that 11% of genes with a good signal in the data display a delay of more than 20 min between completing transcription and mature mRNA production. The genes displaying these long delays are significantly more likely to be short. We also find a statistical association between high delay and late intron retention in pre-mRNA data, indicating significant splicing-associated production delays in many genes.
Journal Article
Joint Modelling of Confounding Factors and Prominent Genetic Regulators Provides Increased Accuracy in Genetical Genomics Studies
Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/.
Journal Article
A Simple Approach to Ranking Differentially Expressed Gene Expression Time Courses through Gaussian Process Regression
Background
The analysis of gene expression from time series underpins many biological studies. Two basic forms of analysis recur for data of this type: removing inactive (quiet) genes from the study and determining which genes are differentially expressed. Often these analysis stages are applied disregarding the fact that the data is drawn from a time series. In this paper we propose a simple model for accounting for the underlying temporal nature of the data based on a Gaussian process.
Results
We review Gaussian process (GP) regression for estimating the continuous trajectories underlying in gene expression time-series. We present a simple approach which can be used to filter quiet genes, or for the case of time series in the form of expression ratios, quantify differential expression. We assess via ROC curves the rankings produced by our regression framework and compare them to a recently proposed hierarchical Bayesian model for the analysis of gene expression time-series (BATS). We compare on both simulated and experimental data showing that the proposed approach considerably outperforms the current state of the art.
Conclusions
Gaussian processes offer an attractive trade-off between efficiency and usability for the analysis of microarray time series. The Gaussian process framework offers a natural way of handling biological replicates and missing values and provides confidence intervals along the estimated curves of gene expression. Therefore, we believe Gaussian processes should be a standard tool in the analysis of gene expression time series.
Journal Article
Warped linear mixed models for the genetic analysis of transformed phenotypes
Linear mixed models (LMMs) are a powerful and established tool for studying genotype–phenotype relationships. A limitation of the LMM is that the model assumes Gaussian distributed residuals, a requirement that rarely holds in practice. Violations of this assumption can lead to false conclusions and loss in power. To mitigate this problem, it is common practice to pre-process the phenotypic values to make them as Gaussian as possible, for instance by applying logarithmic or other nonlinear transformations. Unfortunately, different phenotypes require different transformations, and choosing an appropriate transformation is challenging and subjective. Here we present an extension of the LMM that estimates an optimal transformation from the observed data. In simulations and applications to real data from human, mouse and yeast, we show that using transformations inferred by our model increases power in genome-wide association studies and increases the accuracy of heritability estimation and phenotype prediction.
Linear mixed models (LMMs) provide a powerful method for studying genotype–phenotype associations. Here the authors present a LMM application that estimates an optimal transformation from observed data and increases the accuracy of heritability estimation and phenotype prediction.
Journal Article
Bottom-up data Trusts: disturbing the ‘one size fits all’ approach to data governance
From the friends we make to the foods we like, via our shopping and sleeping habits, most aspects of our quotidian lives can now be turned into machine-readable data points. This article proceeds from an analysis of the very particular type of vulnerability concomitant with our ‘leaking’ data on a daily basis, to show that data ownership is both unlikely and inadequate as an answer to the problems at stake. We also argue that the current construction of top-down regulatory constraints on contractual freedom is both necessary and insufficient. To address the particular type of vulnerability at stake, bottom-up empowerment structures are needed. The latter aim to ‘give a voice’ to data subjects whose choices when it comes to data governance are often reduced to binary, ill-informed consent.
Journal Article
Model-based method for transcription factor target identification with limited data
We present a computational method for identifying potential targets of a transcription factor (TF) using wild-type gene expression time series data. For each putative target gene we fit a simple differential equation model of transcriptional regulation, and the model likelihood serves as a score to rank targets. The expression profile of the TF is modeled as a sample from a Gaussian process prior distribution that is integrated out using a nonparametric Bayesian procedure. This results in a parsimonious model with relatively few parameters that can be applied to short time series datasets without noticeable overfitting. We assess our method using genome-wide chromatin immunoprecipitation (ChIP-chip) and loss-of-function mutant expression data for two TFs, Twist, and Mef2, controlling mesoderm development in DROSOPHILA: Lists of top-ranked genes identified by our method are significantly enriched for genes close to bound regions identified in the ChIP-chip data and for genes that are differentially expressed in loss-of-function mutants. Targets of Twist display diverse expression profiles, and in this case a model-based approach performs significantly better than scoring based on correlation with TF expression. Our approach is found to be comparable or superior to ranking based on mutant differential expression scores. Also, we show how integrating complementary wild-type spatial expression data can further improve target ranking performance.
Journal Article
Hierarchical Bayesian modelling of gene expression time series across irregularly sampled replicates and clusters
Background
Time course data from microarrays and high-throughput sequencing experiments require simple, computationally efficient and powerful statistical models to extract meaningful biological signal, and for tasks such as data fusion and clustering. Existing methodologies fail to capture either the temporal or replicated nature of the experiments, and often impose constraints on the data collection process, such as regularly spaced samples, or similar sampling schema across replications.
Results
We propose hierarchical Gaussian processes as a general model of gene expression time-series, with application to a variety of problems. In particular, we illustrate the method’s capacity for missing data imputation, data fusion and clustering.The method can impute data which is missing both
systematically
and
at random
: in a hold-out test on real data, performance is significantly better than commonly used imputation methods. The method’s ability to model inter- and intra-cluster variance leads to more biologically meaningful clusters. The approach removes the necessity for evenly spaced samples, an advantage illustrated on a developmental Drosophila dataset with irregular replications.
Conclusion
The hierarchical Gaussian process model provides an excellent statistical basis for several gene-expression time-series tasks. It has only a few additional parameters over a regular GP, has negligible additional complexity, is easily implemented and can be integrated into several existing algorithms. Our experiments were implemented in python, and are available from the authors’ website:
http://staffwww.dcs.shef.ac.uk/people/J.Hensman/
.
Journal Article
Detecting periodicities with Gaussian processes
We consider the problem of detecting and quantifying the periodic component of a function given noise-corrupted observations of a limited number of input/output tuples. Our approach is based on Gaussian process regression, which provides a flexible non-parametric framework for modelling periodic data. We introduce a novel decomposition of the covariance function as the sum of periodic and aperiodic kernels. This decomposition allows for the creation of sub-models which capture the periodic nature of the signal and its complement. To quantify the periodicity of the signal, we derive a periodicity ratio which reflects the uncertainty in the fitted sub-models. Although the method can be applied to many kernels, we give a special emphasis to the Matérn family, from the expression of the reproducing kernel Hilbert space inner product to the implementation of the associated periodic kernels in a Gaussian process toolkit. The proposed method is illustrated by considering the detection of periodically expressed genes in the arabidopsis genome.
Journal Article