4,264 research outputs found
Exploring missing heritability in neurodevelopmental disorders:Learning from regulatory elements
In this thesis, I aimed to solve part of the missing heritability in neurodevelopmental disorders, using computational approaches. Next to the investigations of a novel epilepsy syndrome and investigations aiming to elucidate the regulation of the gene involved, I investigated and prioritized genomic sequences that have implications in gene regulation during the developmental stages of human brain, with the goal to create an atlas of high confidence non-coding regulatory elements that future studies can assess for genetic variants in genetically unexplained individuals suffering from neurodevelopmental disorders that are of suspected genetic origin
Enhanced transformer long short-term memory framework for datastream prediction
In machine learning, datastream prediction is a challenging issue, particularly when dealing with enormous amounts of continuous data. The dynamic nature of data makes it difficult for traditional models to handle and sustain real-time prediction accuracy. This research uses a multi-processor long short-term memory (MPLSTM) architecture to present a unique framework for datastream regression. By employing several central processing units (CPUs) to divide the datastream into multiple parallel chunks, the MPLSTM framework illustrates the intrinsic parallelism of long short-term memory (LSTM) networks. The MPLSTM framework ensures accurate predictions by skillfully learning and adapting to changing data distributions. Extensive experimental assessments on real-world datasets have demonstrated the clear superiority of the MPLSTM architecture over previous methods. This study uses the transformer, the most recent deep learning breakthrough technology, to demonstrate how well it can handle challenging tasks and emphasizes its critical role as a cutting-edge approach to raising the bar for machine learning
Inter-individual variation of the human epigenome & applications
Genome-wide association studies (GWAS) have led to the discovery of genetic variants influencing human phenotypes in health and disease. However, almost two decades later, most human traits can still not be accurately predicted from common genetic variants. Moreover, genetic variants discovered via GWAS mostly map to the non-coding genome and have historically resisted interpretation via mechanistic models. Alternatively, the epigenome lies in the cross-roads between genetics and the environment. Thus, there is great excitement towards the mapping of epigenetic inter-individual variation since its study may link environmental factors to human traits that remain unexplained by genetic variants. For instance, the environmental component of the epigenome may serve as a source of biomarkers for accurate, robust and interpretable phenotypic prediction on low-heritability traits that cannot be attained by classical genetic-based models. Additionally, its research may provide mechanisms of action for genetic associations at non-coding regions that mediate their effect via the epigenome. The aim of this thesis was to explore epigenetic inter-individual variation and to mitigate some of the methodological limitations faced towards its future valorisation.Chapter 1 is dedicated to the scope and aims of the thesis. It begins by describing historical milestones and basic concepts in human genetics, statistical genetics, the heritability problem and polygenic risk scores. It then moves towards epigenetics, covering the several dimensions it encompasses. It subsequently focuses on DNA methylation with topics like mitotic stability, epigenetic reprogramming, X-inactivation or imprinting. This is followed by concepts from epigenetic epidemiology such as epigenome-wide association studies (EWAS), epigenetic clocks, Mendelian randomization, methylation risk scores and methylation quantitative trait loci (mQTL). The chapter ends by introducing the aims of the thesis.Chapter 2 focuses on stochastic epigenetic inter-individual variation resulting from processes occurring post-twinning, during embryonic development and early life. Specifically, it describes the discovery and characterisation of hundreds of variably methylated CpGs in the blood of healthy adolescent monozygotic (MZ) twins showing equivalent variation among co-twins and unrelated individuals (evCpGs) that could not be explained only by measurement error on the DNA methylation microarray. DNA methylation levels at evCpGs were shown to be stable short-term but susceptible to aging and epigenetic drift in the long-term. The identified sites were significantly enriched at the clustered protocadherin loci, known for stochastic methylation in neurons in the context of embryonic neurodevelopment. Critically, evCpGs were capable of clustering technical and longitudinal replicates while differentiating young MZ twins. Thus, discovered evCpGs can be considered as a first prototype towards universal epigenetic fingerprint, relevant in the discrimination of MZ twins for forensic purposes, currently impossible with standard DNA profiling. Besides, DNA methylation microarrays are the preferred technology for EWAS and mQTL mapping studies. However, their probe design inherently assumes that the assayed genomic DNA is identical to the reference genome, leading to genetic artifacts whenever this assumption is not fulfilled. Building upon the previous experience analysing microarray data, Chapter 3 covers the development and benchmarking of UMtools, an R-package for the quantification and qualification of genetic artifacts on DNA methylation microarrays based on the unprocessed fluorescence intensity signals. These tools were used to assemble an atlas on genetic artifacts encountered on DNA methylation microarrays, including interactions between artifacts or with X-inactivation, imprinting and tissue-specific regulation. Additionally, to distinguish artifacts from genuine epigenetic variation, a co-methylation-based approach was proposed. Overall, this study revealed that genetic artifacts continue to filter through into the reported literature since current methodologies to address them have overlooked this challenge.Furthermore, EWAS, mQTL and allele-specific methylation (ASM) mapping studies have all been employed to map epigenetic variation but require matching phenotypic/genotypic data and can only map specific components of epigenetic inter-individual variation. Inspired by the previously proposed co-methylation strategy, Chapter 4 describes a novel method to simultaneously map inter-haplotype, inter-cell and inter-individual variation without these requirements. Specifically, binomial likelihood function-based bootstrap hypothesis test for co-methylation within reads (Binokulars) is a randomization test that can identify jointly regulated CpGs (JRCs) from pooled whole genome bisulfite sequencing (WGBS) data by solely relying on joint DNA methylation information available in reads spanning multiple CpGs. Binokulars was tested on pooled WGBS data in whole blood, sperm and combined, and benchmarked against EWAS and ASM. Our comparisons revealed that Binokulars can integrate a wide range of epigenetic phenomena under the same umbrella since it simultaneously discovered regions associated with imprinting, cell type- and tissue-specific regulation, mQTL, ageing or even unknown epigenetic processes. Finally, we verified examples of mQTL and polymorphic imprinting by employing another novel tool, JRC_sorter, to classify regions based on epigenotype models and non-pooled WGBS data in cord blood. In the future, we envision how this cost-effective approach can be applied on larger pools to simultaneously highlight regions of interest in the methylome, a highly relevant task in the light of the post-GWAS era.Moving towards future applications of epigenetic inter-individual variation, Chapters 5 and 6 are dedicated to solving some of methodological issues faced in translational epigenomics.Firstly, due to its simplicity and well-known properties, linear regression is the starting point methodology when performing prediction of a continuous outcome given a set of predictors. However, linear regression is incompatible with missing data, a common phenomenon and a huge threat to the integrity of data analysis in empirical sciences, including (epi)genomics. Chapter 5 describes the development of combinatorial linear models (cmb-lm), an imputation-free, CPU/RAM-efficient and privacy-preserving statistical method for linear regression prediction on datasets with missing values. Cmb-lm provide prediction errors that take into account the pattern of missing values in the incomplete data, even at extreme missingness. As a proof-of-concept, we tested cmb-lm in the context of epigenetic ageing clocks, one of the most popular applications of epigenetic inter-individual variation. Overall, cmb-lm offer a simple and flexible methodology with a wide range of applications that can provide a smooth transition towards the valorisation of linear models in the real world, where missing data is almost inevitable. Beyond microarrays, due to its high accuracy, reliability and sample multiplexing capabilities, massively parallel sequencing (MPS) is currently the preferred methodology of choice to translate prediction models for traits of interests into practice. At the same time, tobacco smoking is a frequent habit sustained by more than 1.3 billion people in 2020 and a leading (and preventable) health risk factor in the modern world. Predicting smoking habits from a persistent biomarker, such as DNA methylation, is not only relevant to account for self-reporting bias in public health and personalized medicine studies, but may also allow broadening forensic DNA phenotyping. Previously, a model to predict whether someone is a current, former, or never smoker had been published based on solely 13 CpGs from the hundreds of thousands included in the DNA methylation microarray. However, a matching lab tool with lower marker throughput, and higher accuracy and sensitivity was missing towards translating the model in practice. Chapter 6 describes the development of an MPS assay and data analysis pipeline to quantify DNA methylation on these 13 smoking-associated biomarkers for the prediction of smoking status. Though our systematic evaluation on DNA standards of known methylation levels revealed marker-specific amplification bias, our novel tool was still able to provide highly accurate and reproducible DNA methylation quantification and smoking habit prediction. Overall, our MPS assay allows the technological transfer of DNA methylation microarray findings and models to practical settings, one step closer towards future applications.Finally, Chapter 7 provides a general discussion on the results and topics discussed across Chapters 2-6. It begins by summarizing the main findings across the thesis, including proposals for follow-up studies. It then covers technical limitations pertaining bisulfite conversion and DNA methylation microarrays, but also more general considerations such as restricted data access. This chapter ends by covering the outlook of this PhD thesis, including topics such as bisulfite-free methods, third-generation sequencing, single-cell methylomics, multi-omics and systems biology.<br/
A comparison and analysis of explainable clinical decision making using white box and black box models
Explainability is a crucial element of machine learning-based making in high stake
scenarios such as risk assessment in criminal justice [80], climate modeling [79], disaster
response [82], education [81] and critical care. There currently exists a performance
tradeoff between low-complexity machine learning models capable of making predictions
that are inherently interpretable (white box) to a human, and cutting-edge high
complexity (black box) models are not readily interpretable.
In this thesis we first aim to assess the reliability of the predictions made by black box
models. We train a series of machine learning models on an ICU (Intensive Care Unit)
outcome prediction task on the MIMIC III dataset. We perform a comparison of the
predictions made by white box models and their black box counterparts by contrasting
explainable model feature coefficients/importances to feature importance values generated
by a post-hoc SHAP (SHapley Additive exPlanation) values. We then validate our results
with a panel of clinical experts. The first study shows that both black box and white box
models prioritize clinically relevant variables when making outcome predictions. Higher
performing models showed prioritizations to more clinically relevant variables than lower
performing models. The black box models show better overall performance than the white
box models. [...
Smart Gas Sensors: Materials, Technologies, Practical ‎Applications, and Use of Machine Learning – A Review
The electronic nose, popularly known as the E-nose, that combines gas sensor arrays (GSAs) with machine learning has gained a strong foothold in gas sensing technology. The E-nose designed to mimic the human olfactory system, is used for the detection and identification of various volatile compounds. The GSAs develop a unique signal fingerprint for each volatile compound to enable pattern recognition using machine learning algorithms. The inexpensive, portable and non-invasive characteristics of the E-nose system have rendered it indispensable within the gas-sensing arena. As a result, E-noses have been widely employed in several applications in the areas of the food industry, health management, disease diagnosis, water and air quality control, and toxic gas leakage detection. This paper reviews the various sensor fabrication technologies of GSAs and highlights the main operational framework of the E-nose system. The paper details vital signal pre-processing techniques of feature extraction, feature selection, in addition to machine learning algorithms such as SVM, kNN, ANN, and Random Forests for determining the type of gas and estimating its concentration in a competitive environment. The paper further explores the potential applications of E-noses for diagnosing diseases, monitoring air quality, assessing the quality of food samples and estimating concentrations of volatile organic compounds (VOCs) in air and in food samples. The review concludes with some challenges faced by E-nose, alternative ways to tackle them and proposes some recommendations as potential future work for further development and design enhancement of E-noses
Design of new algorithms for gene network reconstruction applied to in silico modeling of biomedical data
Programa de Doctorado en BiotecnologĂa, IngenierĂa y TecnologĂa QuĂmicaLĂnea de InvestigaciĂłn: IngenierĂa, Ciencia de Datos y BioinformáticaClave Programa: DBICĂłdigo LĂnea: 111The root causes of disease are still poorly understood. The success of current therapies is limited because persistent diseases are frequently treated based on their symptoms rather than the underlying cause of the disease. Therefore, biomedical research is experiencing a technology-driven shift to data-driven holistic approaches to better characterize the molecular mechanisms causing disease. Using omics data as an input, emerging disciplines like network biology attempt to model the relationships between biomolecules. To this effect, gene co- expression networks arise as a promising tool for deciphering the relationships between genes in large transcriptomic datasets. However, because of their low specificity and high false positive rate, they demonstrate a limited capacity to retrieve the disrupted mechanisms that lead to disease onset, progression, and maintenance. Within the context of statistical modeling, we dove deeper into the reconstruction of gene co-expression networks with the specific goal of discovering disease-specific features directly from expression data. Using ensemble techniques, which combine the results of various metrics, we were able to more precisely capture biologically significant relationships between genes. We were able to find de novo potential disease-specific features with the help of prior biological knowledge and the development of new network inference techniques.
Through our different approaches, we analyzed large gene sets across multiple samples and used gene expression as a surrogate marker for the inherent biological processes, reconstructing robust gene co-expression networks that are simple to explore. By mining disease-specific gene co-expression networks we come up with a useful framework for identifying new omics-phenotype associations from conditional expression datasets.In this sense, understanding diseases from the perspective of biological network perturbations will improve personalized medicine, impacting rational biomarker discovery, patient stratification and drug design, and ultimately leading to more targeted therapies.Universidad Pablo de Olavide de Sevilla. Departamento de Deporte e Informátic
Unveiling the frontiers of deep learning: innovations shaping diverse domains
Deep learning (DL) enables the development of computer models that are
capable of learning, visualizing, optimizing, refining, and predicting data. In
recent years, DL has been applied in a range of fields, including audio-visual
data processing, agriculture, transportation prediction, natural language,
biomedicine, disaster management, bioinformatics, drug design, genomics, face
recognition, and ecology. To explore the current state of deep learning, it is
necessary to investigate the latest developments and applications of deep
learning in these disciplines. However, the literature is lacking in exploring
the applications of deep learning in all potential sectors. This paper thus
extensively investigates the potential applications of deep learning across all
major fields of study as well as the associated benefits and challenges. As
evidenced in the literature, DL exhibits accuracy in prediction and analysis,
makes it a powerful computational tool, and has the ability to articulate
itself and optimize, making it effective in processing data with no prior
training. Given its independence from training data, deep learning necessitates
massive amounts of data for effective analysis and processing, much like data
volume. To handle the challenge of compiling huge amounts of medical,
scientific, healthcare, and environmental data for use in deep learning, gated
architectures like LSTMs and GRUs can be utilized. For multimodal learning,
shared neurons in the neural network for all activities and specialized neurons
for particular tasks are necessary.Comment: 64 pages, 3 figures, 3 table
- …