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Register a new userPoly-Omic Prediction of Complex Traits: OmicKriging
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High-confidence prediction of complex traits such as disease risk or drug response is an ultimate goal of personalized medicine. Although genome-wide association studies have discovered thousands of well-replicated polymorphisms associated with a broad spectrum of complex traits, the combined predictive power of these associations for any given trait is generally too low to be of clinical relevance. We propose a novel systems approach to complex trait prediction, which leverages and integrates similarity in genetic, transcriptomic or other omics-level data. We translate the omic similarity into phenotypic similarity using a method called Kriging, commonly used in geostatistics and machine learning. Our method called OmicKriging emphasizes the use of a wide variety of systems-level data, such as those increasingly made available by comprehensive surveys of the genome, transcriptome and epigenome, for complex trait prediction. Furthermore, our OmicKriging framework allows easy integration of prior information on the function of subsets of omics-level data from heterogeneous sources without the sometimes heavy computational burden of Bayesian approaches. Using seven disease datasets from the Wellcome Trust Case Control Consortium (WTCCC), we show that OmicKriging allows simple integration of sparse and highly polygenic components yielding comparable performance at a fraction of the computing time of a recently published Bayesian sparse linear mixed model method. Using a cellular growth phenotype, we show that integrating mRNA and microRNA expression data substantially increases performance over either dataset alone. We also integrate genotype and expression data to predict change in LDL cholesterol levels after statin treatment and show that OmicKriging performs better than the polygenic score method. We provide an R package to implement OmicKriging.
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Next-generation RNA sequencing (RNA-seq) technology has been widely used to assess full-length RNA isoform abundance in a high-throughput manner. RNA-seq data offer insight into gene expression levels and transcriptome structures, enabling us to better understand the regulation of gene expression and fundamental biological processes. Accurate isoform quantification from RNA-seq data is challenging due to the information loss in sequencing experiments. A recent accumulation of multiple RNA-seq data sets from the same tissue or cell type provides new opportunities to improve the accuracy of isoform quantification. However, existing statistical or computational methods for multiple RNA-seq samples either pool the samples into one sample or assign equal weights to the samples when estimating isoform abundance. These methods ignore the possible heterogeneity in the quality of different samples and could result in biased and unrobust estimates. In this article, we develop a method, which we call joint modeling of multiple RNA-seq samples for accurate isoform quantification (MSIQ), for more accurate and robust isoform quantification by integrating multiple RNA-seq samples under a Bayesian framework. Our method aims to (1) identify a consistent group of samples with homogeneous quality and (2) improve isoform quantification accuracy by jointly modeling multiple RNA-seq samples by allowing for higher weights on the consistent group. We show that MSIQ provides a consistent estimator of isoform abundance, and we demonstrate the accuracy and effectiveness of MSIQ compared with alternative methods through simulation studies on D. melanogaster genes. We justify MSIQs advantages over existing approaches via application studies on real RNA-seq data from human embryonic stem cells, brain tissues, and the HepG2 immortalized cell line.
Alzheimers disease is the most common cause of dementia. It is the fifth-leading cause of death among elderly people. With high genetic heritability (79%), finding disease causal genes is a crucial step in find treatment for AD. Following the International Genomics of Alzheimers Project (IGAP), many disease-associated genes have been identified; however, we dont have enough knowledge about how those disease-associated genes affect gene expression and disease-related pathways. We integrated GWAS summary data from IGAP and five different expression level data by using TWAS method and identified 15 disease causal genes under strict multiple testing (alpha<0.05), 4 genes are newly identified; identified additional 29 potential disease causal genes under false discovery rate(alpha < 0.05), 21 of them are newly identified. Many genes we identified are also associated with some autoimmune disorder.
In this paper we propose network methodology to infer prognostic cancer biomarkers based on the epigenetic pattern DNA methylation. Epigenetic processes such as DNA methylation reflect environmental risk factors, and are increasingly recognised for their fundamental role in diseases such as cancer. DNA methylation is a gene-regulatory pattern, and hence provides a means by which to assess genomic regulatory interactions. Network models are a natural way to represent and analyse groups of such interactions. The utility of network models also increases as the quantity of data and number of variables increase, making them increasingly relevant to large-scale genomic studies. We propose methodology to infer prognostic genomic networks from a DNA methylation-based measure of genomic interaction and association. We then show how to identify prognostic biomarkers from such networks, which we term `network community oncomarkers. We illustrate the power of our proposed methodology in the context of a large publicly available breast cancer dataset.
Traumatic brain injury can be caused by various types of head impacts. However, due to different kinematic characteristics, many brain injury risk estimation models are not generalizable across the variety of impacts that humans may sustain. The current definitions of head impact subtypes are based on impact sources (e.g., football, traffic accident), which may not reflect the intrinsic kinematic similarities of impacts across the impact sources. To investigate the potential new definitions of impact subtypes based on kinematics, 3,161 head impacts from various sources including simulation, college football, mixed martial arts, and car racing were collected. We applied the K-means clustering to cluster the impacts on 16 standardized temporal features from head rotation kinematics. Then, we developed subtype-specific ridge regression models for cumulative strain damage (using the threshold of 15%), which significantly improved the estimation accuracy compared with the baseline method which mixed impacts from different sources and developed one model (R^2 from 0.7 to 0.9). To investigate the effect of kinematic features, we presented the top three critical features (maximum resultant angular acceleration, maximum angular acceleration along the z-axis, maximum linear acceleration along the y-axis) based on regression accuracy and used logistic regression to find the critical points for each feature that partitioned the subtypes. This study enables researchers to define head impact subtypes in a data-driven manner, which leads to more generalizable brain injury risk estimation.
Motivation : Molecular signatures for diagnosis or prognosis estimated from large-scale gene expression data often lack robustness and stability, rendering their biological interpretation challenging. Increasing the signatures interpretability and stability across perturbations of a given dataset and, if possible, across datasets, is urgently needed to ease the discovery of important biological processes and, eventually, new drug targets. Results : We propose a new method to construct signatures with increased stability and easier interpretability. The method uses a gene network as side interpretation and enforces a large connectivity among the genes in the signature, leading to signatures typically made of genes clustered in a few subnetworks. It combines the recently proposed graph Lasso procedure with a stability selection procedure. We evaluate its relevance for the estimation of a prognostic signature in breast cancer, and highlight in particular the increase in interpretability and stability of the signature.
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