%0 Journal Article %J Am J Hum Genet %D 2019 %T ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies. %A Liu, Yaowu %A Chen, Sixing %A Li, Zilin %A Morrison, Alanna C %A Eric Boerwinkle %A Lin, Xihong %K Algorithms %K Computer Simulation %K Data Interpretation, Statistical %K Disease %K Genetic Association Studies %K Genetic Variation %K Genome, Human %K Humans %K Models, Genetic %K Sequence Analysis, DNA %X

Set-based analysis that jointly tests the association of variants in a group has emerged as a popular tool for analyzing rare and low-frequency variants in sequencing studies. The existing set-based tests can suffer significant power loss when only a small proportion of variants are causal, and their powers can be sensitive to the number, effect sizes, and effect directions of the causal variants and the choices of weights. Here we propose an aggregated Cauchy association test (ACAT), a general, powerful, and computationally efficient p value combination method for boosting power in sequencing studies. First, by combining variant-level p values, we use ACAT to construct a set-based test (ACAT-V) that is particularly powerful in the presence of only a small number of causal variants in a variant set. Second, by combining different variant-set-level p values, we use ACAT to construct an omnibus test (ACAT-O) that combines the strength of multiple complimentary set-based tests, including the burden test, sequence kernel association test (SKAT), and ACAT-V. Through analysis of extensively simulated data and the whole-genome sequencing data from the Atherosclerosis Risk in Communities (ARIC) study, we demonstrate that ACAT-V complements the SKAT and the burden test, and that ACAT-O has a substantially more robust and higher power than those of the alternative tests.

%B Am J Hum Genet %V 104 %P 410-421 %8 2019 Mar 07 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30849328?dopt=Abstract %R 10.1016/j.ajhg.2019.01.002 %0 Journal Article %J Stroke %D 2015 %T Genetic overlap between diagnostic subtypes of ischemic stroke. %A Holliday, Elizabeth G %A Traylor, Matthew %A Malik, Rainer %A Bevan, Steve %A Falcone, Guido %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Cotlarciuc, Ioana %A Bis, Joshua C %A Boerwinkle, Eric %A Boncoraglio, Giorgio B %A Clarke, Robert %A Cole, John W %A Fornage, Myriam %A Furie, Karen L %A Ikram, M Arfan %A Jannes, Jim %A Kittner, Steven J %A Lincz, Lisa F %A Maguire, Jane M %A Meschia, James F %A Mosley, Thomas H %A Nalls, Mike A %A Oldmeadow, Christopher %A Parati, Eugenio A %A Psaty, Bruce M %A Rothwell, Peter M %A Seshadri, Sudha %A Scott, Rodney J %A Sharma, Pankaj %A Sudlow, Cathie %A Wiggins, Kerri L %A Worrall, Bradford B %A Rosand, Jonathan %A Mitchell, Braxton D %A Dichgans, Martin %A Markus, Hugh S %A Levi, Christopher %A Attia, John %A Wray, Naomi R %K Alleles %K Atherosclerosis %K Cerebral Small Vessel Diseases %K Cohort Studies %K Data Interpretation, Statistical %K Embolism %K Genome-Wide Association Study %K Genotype %K Humans %K Ischemia %K Linear Models %K Meta-Analysis as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Stroke %X

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

%B Stroke %V 46 %P 615-9 %8 2015 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract %R 10.1161/STROKEAHA.114.007930 %0 Journal Article %J Epilepsy Res %D 2011 %T Cortical sulcal areas in baboons (Papio hamadryas spp.) with generalized interictal epileptic discharges on scalp EEG. %A Szabó, C A %A Kochunov, P %A Knape, K D %A McCoy, K J M %A Leland, M M %A Lancaster, J L %A Fox, P T %A Williams, J T %A Rogers, J %K Animals %K Brain %K Cerebral Cortex %K Data Interpretation, Statistical %K Electroencephalography %K Epilepsy %K Female %K Functional Laterality %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Papio %K Parietal Lobe %K Seizures %X

Brain MRI studies in people with idiopathic generalized epilepsies demonstrate regional morphometric differences, though variable in magnitude and location. As the baboon provides an excellent electroclinical and neuroimaging model for photosensitive generalized epilepsy in humans, this study evaluated MRI volumetric and morphometric differences between baboons with interictal epileptic discharges (IEDs) on scalp EEG and baboons with normal EEG studies. Seventy-seven baboons underwent high-resolution brain MRI and scalp EEG studies. The scans were acquired using an 8-channel primate head coil (Siemens TRIO 3T scanner, Erlangen, Germany). After spatial normalization, sulcal measurements were obtained by object-based-morphology methods. One-hour scalp EEG studies were performed in animals sedated with ketamine. Thirty-eight (22F/16M) baboons had normal EEGs (IED-), while 39 (22F/17M) had generalized IEDs (IED+). The two groups were compared for age, total brain volume, and sulcal areas (Hotelling's Trace) as well as between-subjects comparison of 11 individual sulcal areas (averaged between left and right hemispheres). There were no differences between IED- and IED+ groups with respect to age or total brain (gray or white matter) volume, and multivariate tests demonstrated a marginally significant decrease of sulcal areas in IED+ baboons (p=0.075). Tests of between-subjects effects showed statistically significant decreases in the intraparietal (p=0.002), central (p=0.03) and cingulate sulci (p=0.02), and marginal decreases involving the lunate (p=0.07) and superior temporal sulci (p=0.08). Differences in sulcal areas in IED+ baboons may reflect global developmental abnormalities, while decreases of areas of specific sulci reflect anatomical markers for potential generators or cortical nodes of the networks underlying spontaneous seizures and photosensitivity in the baboon.

%B Epilepsy Res %V 93 %P 91-5 %8 2011 Feb %G eng %N 2-3 %1 https://www.ncbi.nlm.nih.gov/pubmed/21256716?dopt=Abstract %R 10.1016/j.eplepsyres.2010.10.016 %0 Journal Article %J Trends Genet %D 2010 %T Personal genome research : what should the participant be told? %A McGuire, Amy L %A Lupski, James R %K Data Interpretation, Statistical %K Genetic Variation %K Genome, Human %K Humans %K Sequence Analysis, DNA %K Truth Disclosure %X

Should the results of whole genome sequencing research be disclosed to participants, in particular when the results have uncertain or indeterminate phenotypic consequences? This controversial question is considered in light of one author's (J.L.) experience as a geneticist who recently had his own genome sequenced.

%B Trends Genet %V 26 %P 199-201 %8 2010 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/20381895?dopt=Abstract %R 10.1016/j.tig.2009.12.007 %0 Journal Article %J J Comput Biol %D 2004 %T Pooled Genomic Indexing (PGI): analysis and design of experiments. %A Csuros, Miklos %A Milosavljevic, Aleksandar %K Animals %K Chromosomes, Artificial, Bacterial %K Computational Biology %K Data Interpretation, Statistical %K Mice %K Phylogeny %K Physical Chromosome Mapping %K Probability %K Rats %K Research Design %X

Pooled Genomic Indexing (PGI) is a novel method for physical mapping of clones onto known sequences. PGI is carried out by pooling arrayed clones and generating shotgun sequence reads from the pools. The shotgun sequences are compared to a reference sequence. In the simplest case, clones are placed on an array and are pooled by rows and columns. If a shotgun sequence from a row pool and another shotgun sequence from a column pool match the reference sequence at a close distance, they are both assigned to the clone at the intersection of the two pools. Accordingly, the clone is mapped onto the region of the reference sequence between the two matches. A probabilistic model for PGI is developed, and several pooling designs are described and analyzed, including transversal designs and designs from linear codes. The probabilistic model and the pooling schemes are validated in simulated experiments where 625 rat bacterial artificial chromosome (BAC) clones and 207 mouse BAC clones are mapped onto homologous human sequence.

%B J Comput Biol %V 11 %P 1001-21 %8 2004 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/15700414?dopt=Abstract %R 10.1089/cmb.2004.11.1001 %0 Journal Article %J AIDS Educ Prev %D 1998 %T Relationship of HIV testing and high-risk behaviors among clients in methadone maintenance treatment. %A Grella, C E %A Campos, M %A Anglin, M D %K Adult %K Data Interpretation, Statistical %K Depression %K Female %K Heroin Dependence %K HIV Infections %K HIV Seropositivity %K Humans %K Logistic Models %K Male %K Methadone %K Risk-Taking %K Sexual Behavior %K Substance Abuse, Intravenous %X

This article reports on the association between frequency of HIV testing and high-risk behaviors among 339 individuals in the Los Angeles Enhanced Methadone Maintenance Project. Individuals who reported taking three or more HIV tests prior to entering treatment (45% of the sample) were more likely to know someone who was HIV positive, to engage in illegal activity, to perceive their risk for HIV as high, and to use condoms; they were less likely to disinfect injection equipment; and they scored higher on measures of HIV knowledge and depression as compared with less frequent testers. The strongest predictor of frequent HIV testing (three or more tests) after treatment entry, reported by 43% of the sample, was having a high number of injection-sharing partners. Although a substantial number of individuals in methadone maintenance treatment continued to take HIV tests, test taking was more strongly related to high-risk injection behavior than to sexual behavior.

%B AIDS Educ Prev %V 10 %P 403-16 %8 1998 Oct %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/9799937?dopt=Abstract