Linear mixed models (LMMs) are widely used for heritability estimation in genome-wide association studies (GWAS). In standard approaches to heritability estimation with LMMs, a genetic relationship matrix (GRM) must be specified. In GWAS, the GRM is frequently a correlation matrix estimated from the study population's genotypes, which corresponds to a normalized Euclidean distance kernel. In this paper, we show that reliance on the Euclidean distance kernel contributes to several unresolved modeling inconsistencies in heritability estimation for GWAS. These inconsistencies can cause biased heritability estimates in the presence of linkage disequilibrium (LD), depending on the distribution of causal variants. We show that these biases can be resolved (at least at the modeling level) if one adopts a Mahalanobis distance-based GRM for LMM analysis. Additionally, we propose a new definition of partitioned heritability -- the heritability attributable to a subset of genes or single nucleotide polymorphisms (SNPs) -- using the Mahalanobis GRM, and show that it inherits many of the nice consistency properties identified in our original analysis. Partitioned heritability is a relatively new area for GWAS analysis, where inconsistency issues related to LD have previously been known to be especially pernicious.
Recently, in independent work, @cite_0 proposed using the Mahalanobis kernel in a similar way for heritability esitmation with GWAS data. 's paper primarily focuses on empirical analysis, using both simulated and real datasets to illsutrate advantages of the Mahalanobis kernel. The present work contains more precise mathematical and statistical justification for much of the work in @cite_0 , and introduces statistical principles (e.g. @math -heritability in Section ) that can be extended to other targeted application areas and genetics (like partitioning heritability).
@cite_0
2289130514 2773459529 2067100182 2156463490
We are interested in the large-scale learning of Mahalanobis distances, with a particular focus on person re-identification. We propose a metric learning formulation called Weighted Approximate Rank Component Analysis (WARCA). WARCA optimizes the precision at top ranks by combining the WARP loss with a regularizer that favors orthonormal linear mappings and avoids rank-deficient embeddings. Using this new regularizer allows us to adapt the large-scale WSABIE procedure and to leverage the Adam stochastic optimization algorithm, which results in an algorithm that scales gracefully to very large data-sets. Also, we derive a kernelized version which allows to take advantage of state-of-the-art features for re-identification when data-set size permits kernel computation. Benchmarks on recent and standard re-identification data-sets show that our method beats existing state-of-the-art techniques both in terms of accuracy and speed. We also provide experimental analysis to shade lights on the properties of the regularizer we use, and how it improves performance. Single nucleotide polymorphism (SNP)-heritability estimation is an important topic in several research fields, including animal, plant and human genetics, as well as in ecology. Linear mixed model estimation of SNP-heritability uses the structures of genomic relationships between individuals, which is constructed from genome-wide sets of SNP-markers that are generally weighted equally in their contributions. Proposed methods to handle dependence between SNPs include, “thinning” the marker set by linkage disequilibrium (LD)-pruning, the use of haplotype-tagging of SNPs, and LD-weighting of the SNP-contributions. For improved estimation, we propose a new conceptual framework for genomic relationship matrix, in which Mahalanobis distance-based LD-correction is used in a linear mixed model estimation of SNP-heritability. The superiority of the presented method is illustrated and compared to mixed-model analyses using a VanRaden genomic relationship matrix, a matrix used by GCTA and a matrix employing LD-weighting (as implemented in the LDAK software) in simulated (using real human, rice and cattle genotypes) and real (maize, rice and mice) datasets. Despite of the computational difficulties, our results suggest that by using the proposed method one can improve the accuracy of SNP-heritability estimates in datasets with high LD. Measures of genomic similarity are often the basis of flexible statistical analyses, and when based on kernel methods, they provide a powerful platform to take advantage of a broad and deep statistical theory, and a wide range of existing software; see the companion paper for a review of this material [1]. The kernel method converts information – perhaps complex or high-dimensional information – for a pair of subjects to a quantitative value representing either similarity or dissimilarity, with the requirement that it must create a positive semidefinite matrix when applied to all pairs of subjects. This approach provides enormous opportunities to enhance genetic analyses by including a wide range of publically-available data as structured kernel ‘prior’ information. Kernel methods are appealing for their generality, yet this generality can make it challenging to formulate measures of similarity that directly address a specific scientific aim, or that are most powerful to detect a specific genetic mechanism. Although it is difficult to create a cook book of kernels for genetic studies, useful guidelines can be gleaned from a variety of novel published approaches. We review some novel developments of kernels for specific analyses and speculate on how to build kernels for complex genomic attributes based on publically available data. The creativity of analysts, with rigorous evaluations by applications to real and simulated data, will ultimately provide a much stronger array of kernel ‘tools’ for genetic analyses. We treat the use of more complex higher degree polynomial curves and surfaces of degree higher than 2, which have many desirable properties for object recognition and position estimation, and attack the instability problem arising in their use with partial and noisy data. The scenario discussed in this paper is one where we have a set of objects that are modeled as implicit polynomial functions, or a set of representations of classes of objects with each object in a class modeled as an implicit polynomial function, stored in the database. Then, given partial data from one of the objects, we want to recognize the object (or the object class) or collect more data in order to get better parameter estimates for more reliable recognition. Two problems arising in this scenario are discussed: 1) the problem of recognizing these polynomials by comparing them in terms of their coefficients; and 2) the problem of where to collect data so as to improve the parameter estimates as quickly as possible. We use an asymptotic Bayesian approximation for solving the two problems. The intrinsic dimensionality of polynomials and the use of the Mahalanobis distance are discussed.