Collaborating Authors

Sparse Instrumental Variables (SPIV) for Genome-Wide Studies

Neural Information Processing Systems

This paper describes a probabilistic framework for studying associations between multiple genotypes, biomarkers, and phenotypic traits in the presence of noise and unobserved confounders for large genetic studies. The framework builds on sparse linear methods developed for regression and modified here for inferring causal structures of richer networks with latent variables. The method is motivated by the use of genotypes as instruments'' to infer causal associations between phenotypic biomarkers and outcomes, without making the common restrictive assumptions of instrumental variable methods. The method may be used for an effective screening of potentially interesting genotype phenotype and biomarker-phenotype associations in genome-wide studies, which may have important implications for validating biomarkers as possible proxy endpoints for early stage clinical trials. Where the biomarkers are gene transcripts, the method can be used for fine mapping of quantitative trait loci (QTLs) detected in genetic linkage studies.

A New Statistical Framework for Genetic Pleiotropic Analysis of High Dimensional Phenotype Data Machine Learning

The widely used genetic pleiotropic analysis of multiple phenotypes are often designed for examining the relationship between common variants and a few phenotypes. They are not suited for both high dimensional phenotypes and high dimensional genotype (next-generation sequencing) data. To overcome these limitations, we develop sparse structural equation models (SEMs) as a general framework for a new paradigm of genetic analysis of multiple phenotypes. To incorporate both common and rare variants into the analysis, we extend the traditional multivariate SEMs to sparse functional SEMs. To deal with high dimensional phenotype and genotype data, we employ functional data analysis and the alternative direction methods of multiplier (ADMM) techniques to reduce data dimension and improve computational efficiency. Using large scale simulations we showed that the proposed methods have higher power to detect true causal genetic pleiotropic structure than other existing methods. Simulations also demonstrate that the gene-based pleiotropic analysis has higher power than the single variant-based pleiotropic analysis. The proposed method is applied to exome sequence data from the NHLBI Exome Sequencing Project (ESP) with 11 phenotypes, which identifies a network with 137 genes connected to 11 phenotypes and 341 edges. Among them, 114 genes showed pleiotropic genetic effects and 45 genes were reported to be associated with phenotypes in the analysis or other cardiovascular disease (CVD) related phenotypes in the literature.

Network-Guided Biomarker Discovery Machine Learning

Identifying measurable genetic indicators (or biomarkers) of a specific condition of a biological system is a key element of precision medicine. Indeed it allows to tailor diagnostic, prognostic and treatment choice to individual characteristics of a patient. In machine learning terms, biomarker discovery can be framed as a feature selection problem on whole-genome data sets. However, classical feature selection methods are usually underpowered to process these data sets, which contain orders of magnitude more features than samples. This can be addressed by making the assumption that genetic features that are linked on a biological network are more likely to work jointly towards explaining the phenotype of interest. We review here three families of methods for feature selection that integrate prior knowledge in the form of networks.

Causal Mediation Analysis Leveraging Multiple Types of Summary Statistics Data Machine Learning

Genome-wide association studies (GWAS) identify statistically significantcorrelations between genetic and phenotypic variables. In the era of Biobank GWAS, phenotypes can be virtually any variables measurable across millions of individuals in the database, of which examples includediagnosis codes, routine laboratory test results, familyhistory of complex disorders, and even socioeconomical status. Significant signals of well-executed GWAS implicate unidirectional causal relationship from the tagged genomic variants to phenotypes, not the other way. In biological information cascade, using GWAS, we can establish links between the very first (genetics) and the last (phenotypes) layers,and we normally expect the effect sizes are typically minuscule; and necessary statistical significance can be achieved in studies involving at least hundreds of thousands of individuals. Nonetheless, a large number of GWAS summary statistics data are already made publicly available.Geneticists have already uncovered more than 24k unique associations between single nucleotide polymorphism (SNP) markers and complex phenotypes [16].

A Sparse Graph-Structured Lasso Mixed Model for Genetic Association with Confounding Correction Machine Learning

While linear mixed model (LMM) has shown a competitive performance in correcting spurious associations raised by population stratification, family structures, and cryptic relatedness, more challenges are still to be addressed regarding the complex structure of genotypic and phenotypic data. For example, geneticists have discovered that some clusters of phenotypes are more co-expressed than others. Hence, a joint analysis that can utilize such relatedness information in a heterogeneous data set is crucial for genetic modeling. We proposed the sparse graph-structured linear mixed model (sGLMM) that can incorporate the relatedness information from traits in a dataset with confounding correction. Our method is capable of uncovering the genetic associations of a large number of phenotypes together while considering the relatedness of these phenotypes. Through extensive simulation experiments, we show that the proposed model outperforms other existing approaches and can model correlation from both population structure and shared signals. Further, we validate the effectiveness of sGLMM in the real-world genomic dataset on two different species from plants and humans. In Arabidopsis thaliana data, sGLMM behaves better than all other baseline models for 63.4% traits. We also discuss the potential causal genetic variation of Human Alzheimer's disease discovered by our model and justify some of the most important genetic loci.