For precision medicine and personalized treatment, we need to identify predictive markers of disease. We focus on Alzheimer's disease (AD), where magnetic resonance imaging scans provide information about the disease status. By combining imaging with genome sequencing, we aim at identifying rare genetic markers associated with quantitative traits predicted from convolutional neural networks (CNNs), which traditionally have been derived manually by experts. Kernel-based tests are a powerful tool for associating sets of genetic variants, but how to optimally model rare genetic variants is still an open research question. We propose a generalized set of kernels that incorporate prior information from various annotations and multi-omics data. In the analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we evaluate whether (i) CNNs yield precise and reliable brain traits, and (ii) the novel kernel-based tests can help to identify loci associated with AD. The results indicate that CNNs provide a fast, scalable and precise tool to derive quantitative AD traits and that new kernels integrating domain knowledge can yield higher power in association tests of very rare variants.
Popular kernel-based tests include FaST-LMM-Set @cite_0 @cite_19 , the sequence kernel association test (SKAT, @cite_7 ) and optimal SKAT (SKAT-O, @cite_4 ), which are based on weighted linear kernels @math @cite_7 @cite_8 @cite_19 , or a linear combination of weighted linear and collapsing kernels @cite_4 . Newer approaches @cite_17 derive further data-adaptive combinations of linear, quadratic, IBS, and collapsing kernels. However, all these kernels provide suboptimal performance for the analysis of very rare genetic variants. Here, linear and quadratic kernels yield uninformative similarity measures (i.e., diagonal kernel matrices for singletons, which are variants with only one observed copy of the minor allele) and collapsing kernels often yield unspecific signals and aggregate noise.
@cite_4 @cite_7 @cite_8 @cite_0 @cite_19 @cite_17
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Analysis of rare genetic variants has focused on region-based analysis wherein a subset of the variants within a genomic region is tested for association with a complex trait. Two important practical challenges have emerged. First, it is difficult to choose which test to use. Second, it is unclear which group of variants within a region should be tested. Both depend on the unknown true state of nature. Therefore, we develop the Multi-Kernel SKAT (MK-SKAT) which tests across a range of rare variant tests and groupings. Specifically, we demonstrate that several popular rare variant tests are special cases of the sequence kernel association test which compares pair-wise similarity in trait value to similarity in the rare variant genotypes between subjects as measured through a kernel function. Choosing a particular test is equivalent to choosing a kernel. Similarly, choosing which group of variants to test also reduces to choosing a kernel. Thus, MK-SKAT uses perturbation to test across a range of kernels. Simulations and real data analyses show that our framework controls type I error while maintaining high power across settings: MK-SKAT loses power when compared to the kernel for a particular scenario but has much greater power than poor choices. SUMMARY With development of massively parallel sequencing technologies, there is a substantial need for developing powerful rare variant association tests. Common approaches include burden and non-burden tests. Burden tests assume all rare variants in the target region have effects on the phenotype in the same direction and of similar magnitude. The recently proposed sequence kernel association test (SKAT) (Wu, M. C., and others, 2011. Rare-variant association testing for sequencing data with the SKAT.The American Journal of HumanGenetics89,82–93],anextensionoftheC-alphatest(Neale,B.M.,andothers,2011.Testingforan unusual distribution of rare variants. PLoS Genetics 7, 161–165], provides a robust test that is particularly powerful in the presence of protective and deleterious variants and null variants, but is less powerful than burden tests when a large number of variants in a region are causal and in the same direction. As the underlying biological mechanisms are unknown in practice and vary from one gene to another across the genome,itisofsubstantialpracticalinteresttodevelopatestthatisoptimalforbothscenarios.Inthispaper, we propose a class of tests that include burden tests and SKAT as special cases, and derive an optimal test within this class that maximizes power. We show that this optimal test outperforms burden tests and SKAT in a wide range of scenarios. The results are illustrated using simulation studies and triglyceride data from the Dallas Heart Study. In addition, we have derived sample size power calculation formula for SKAT with a new family of kernels to facilitate designing new sequence association studies. Purpose – The purpose of this paper is to suggest an alternative to the widely used Times Cited criterion for analysing citation networks. The approach involves taking account of the natures of the papers that cite a given paper, so as to differentiate between papers that attract the same number of citations.Design methodology approach – ArticleRank is an algorithm that has been derived from Google's PageRank algorithm to measure the influence of journal articles. ArticleRank is applied to two datasets – a citation network based on an early paper on webometrics, and a self‐citation network based on the 19 most cited papers in the Journal of Documentation – using citation data taken from the Web of Knowledge database.Findings – ArticleRank values provide a different ranking of a set of papers from that provided by the corresponding Times Cited values, and overcomes the inability of the latter to differentiate between papers with the same numbers of citations. The difference in rankings between Times Cited ... A citing sentence is one that appears in a scientific article and cites previous work. Citing sentences have been studied and used in many applications. For example, they have been used in scientific paper summarization, automatic survey generation, paraphrase identification, and citation function classification. Citing sentences that cite multiple papers are common in scientific writing. This observation should be taken into consideration when using citing sentences in applications. For instance, when a citing sentence is used in a summary of a scientific paper, only the fragments of the sentence that are relevant to the summarized paper should be included in the summary. In this paper, we present and compare three different approaches for identifying the fragments of a citing sentence that are related to a given target reference. Our methods are: word classification, sequence labeling, and segment classification. Our experiments show that segment classification achieves the best results.