@article {214, title = {Covariate-modulated local false discovery rate for genome-wide association studies.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Aug 1}, pages = {2098-104}, abstract = {

MOTIVATION: Genome-wide association studies (GWAS) have largely failed to identify most of the genetic basis of highly heritable diseases and complex traits. Recent work has suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS, given currently obtainable sample sizes. In this scenario, Bonferroni-derived thresholds are severely underpowered to detect the vast majority of associations. Local false discovery rate (fdr) methods provide more power to detect non-null associations, but implicit assumptions about the exchangeability of single nucleotide polymorphisms (SNPs) limit their ability to discover non-null loci.

METHODS: We propose a novel covariate-modulated local false discovery rate (cmfdr) that incorporates prior information about gene element-based functional annotations of SNPs, so that SNPs from categories enriched for non-null associations have a lower fdr for a given value of a test statistic than SNPs in unenriched categories. This readjustment of fdr based on functional annotations is achieved empirically by fitting a covariate-modulated parametric two-group mixture model. The proposed cmfdr methodology is applied to a large Crohn{\textquoteright}s disease GWAS.

RESULTS: Use of cmfdr dramatically improves power, e.g. increasing the number of loci declared significant at the 0.05 fdr level by a factor of 5.4. We also demonstrate that SNPs were declared significant using cmfdr compared with usual fdr replicate in much higher numbers, while maintaining similar replication rates for a given fdr cutoff in de novo samples, using the eight Crohn{\textquoteright}s disease substudies as independent training and test datasets. Availability an implementation: https://sites.google.com/site/covmodfdr/

CONTACT: : wes.stat@gmail.com

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Analysis of Variance, Bayes Theorem, Computational Biology, False Positive Reactions, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu145}, author = {Zablocki, Rong W and Schork, Andrew J and Levine, Richard A and Andreassen, Ole A and Dale, Anders M and Thompson, Wesley K} } @article {211, title = {Accumulation of neural activity in the posterior insula encodes the passage of time.}, journal = {Neuropsychologia}, volume = {48}, year = {2010}, month = {2010 Aug}, pages = {3110-20}, abstract = {

A number of studies have examined the perception of time with durations ranging from milliseconds to a few seconds, however the neural basis of these processes are still poorly understood and the neural substrates underlying the perception of multiple-second intervals are unknown. Here we present evidence of neural systems activity in circumscribed areas of the human brain involved in the encoding of intervals with durations of 9 and 18s in a temporal reproduction task using event-related functional magnetic resonance imaging (fMRI). During the encoding there was greater activation in more posterior parts of the medial frontal and insular cortex whereas the reproduction phase involved more anterior parts of these brain structures. Intriguingly, activation curves over time show an accumulating pattern of neural activity, which peaks at the end of the interval within bilateral posterior insula and superior temporal cortex when individuals are presented with 9- and 18-s tone intervals. This is consistent with an accumulator-type activity, which encodes duration in the multiple seconds range. Given the close connection between the dorsal posterior insula and ascending internal body signals, we suggest that the accumulation of physiological changes in body states constitutes our experience of time. This is the first time that an accumulation function in the posterior insula is detected that might be correlated with the encoding of time intervals.

}, keywords = {Adult, Analysis of Variance, Brain Mapping, Cerebral Cortex, Factor Analysis, Statistical, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Oxygen, Reaction Time, Time Factors, Time Perception, Young Adult}, issn = {1873-3514}, doi = {10.1016/j.neuropsychologia.2010.06.023}, author = {Wittmann, Marc and Simmons, Alan N and Aron, Jennifer L and Paulus, Martin P} } @article {194, title = {Atypical face versus object processing and hemispheric asymmetries in 10-month-old infants at risk for autism.}, journal = {Biol Psychiatry}, volume = {66}, year = {2009}, month = {2009 Nov 15}, pages = {950-7}, abstract = {

BACKGROUND: Previous studies have documented atypicalities in face/object processing in children and adults with autism spectrum disorders (ASDs). To investigate whether such atypicalities may reflect a genetically mediated risk factor present early in development, we measured face/object processing in 10-month-old high-risk infants who carry some of the genes associated with ASD because they have an older sibling diagnosed with the disorder.

METHODS: We employed event-related potentials (ERPs) to measure cortical responses to pictures of faces and objects, the objects being toys. Latencies and amplitudes of four ERP components (P100, N290, P400, and Nc) were compared between 20 high-risk infants and 20 low-risk control subjects (infants with no family history of ASD).

RESULTS: Responses to faces versus objects differed between high- and low-risk infants for the latencies of the N290 and P400. Differences were driven by faster responses to faces than objects in low-risk, but not high-risk, infants (P400) and, conversely, faster responses to objects than faces in high-risk, but not low-risk, infants (N290). Object responses were also faster in high-risk than low-risk infants (both N290 and P400). Left versus right hemisphere responses also differed between high- and low-risk infants for the amplitudes of the P100, N290, and P400; collapsed across faces/objects, low-risk, but not high-risk, infants exhibited hemisphere asymmetries.

CONCLUSIONS: Genetic risk for ASD is associated with atypical face versus object processing and an atypical lack of hemispheric asymmetry early in life. These atypicalities might contribute to development of the disorder.

}, keywords = {Analysis of Variance, Autistic Disorder, Brain, Brain Mapping, Cerebral Cortex, Child, Child, Preschool, Electroencephalography, Evoked Potentials, Face, Female, Fourier Analysis, Functional Laterality, Humans, Infant, Male, Neuropsychological Tests, Pattern Recognition, Visual, Photic Stimulation, Reaction Time, Risk}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2009.07.031}, author = {McCleery, Joseph P and Akshoomoff, Natacha and Dobkins, Karen R and Carver, Leslie J} } @article {184, title = {Effects of gestational length, gender, postnatal age, and birth order on visual contrast sensitivity in infants.}, journal = {J Vis}, volume = {9}, year = {2009}, month = {2009}, pages = {19.1-21}, abstract = {

To investigate effects of visual experience versus preprogrammed mechanisms on visual development, we used multiple regression analysis to determine the extent to which a variety of variables (that differ in the extent to which they are tied to visual experience) predict luminance and chromatic (red/green) contrast sensitivity (CS), which are mediated by the magnocellular (M) and parvocellular (P) subcortical pathways, respectively. Our variables included gestational length (GL), birth weight (BW), gender, postnatal age (PNA), and birth order (BO). Two-month-olds (n = 60) and 6-month-olds (n = 122) were tested. Results revealed that (1) at 2 months, infants with longer GL have higher luminance CS; (2) at both ages, CS significantly increases over a approximately 21-day range of PNA, but this effect is stronger in 2- than 6-month-olds and stronger for chromatic than luminance CS; (3) at 2 months, boys have higher luminance CS than girls; and (4) at 2 months, firstborn infants have higher CS, while at 6 months, non-firstborn infants have higher CS. The results for PNA/GL are consistent with the possibility that P pathway development is more influenced by variables tied to visual experience (PNA), while M pathway development is more influenced by variables unrelated to visual experience (GL). Other variables, including prenatal environment, are also discussed.

}, keywords = {Age Factors, Analysis of Variance, Birth Order, Color Perception, Contrast Sensitivity, Female, Gender Identity, Gestational Age, Humans, Infant, Light, Male, Regression Analysis}, issn = {1534-7362}, doi = {10.1167/9.10.19}, author = {Dobkins, Karen R and Bosworth, Rain G and McCleery, Joseph P} } @article {143, title = {Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila.}, journal = {Nat Neurosci}, volume = {10}, year = {2007}, month = {2007 Sep}, pages = {1160-7}, abstract = {

Epidermal growth factor receptor (EGFR) signaling in the mammalian hypothalamus is important in the circadian regulation of activity. We have examined the role of this pathway in the regulation of sleep in Drosophila melanogaster. Our results demonstrate that rhomboid (Rho)- and Star-mediated activation of EGFR and ERK signaling increases sleep in a dose-dependent manner, and that blockade of rhomboid (rho) expression in the nervous system decreases sleep. The requirement of rho for sleep localized to the pars intercerebralis, a part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates. These results suggest that sleep and its regulation by EGFR signaling may be ancestral to insects and mammals.

}, keywords = {Analysis of Variance, Animals, Animals, Genetically Modified, Behavior, Animal, Drosophila, Drosophila Proteins, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Developmental, Membrane Proteins, Motor Activity, Receptor, Epidermal Growth Factor, Signal Transduction, Sleep}, issn = {1097-6256}, doi = {10.1038/nn1957}, author = {Foltenyi, Krisztina and Greenspan, Ralph J and Newport, John W} } @article {144, title = {Serotonin and neuropeptide F have opposite modulatory effects on fly aggression.}, journal = {Nat Genet}, volume = {39}, year = {2007}, month = {2007 May}, pages = {678-82}, abstract = {

Both serotonin (5-HT) and neuropeptide Y have been shown to affect a variety of mammalian behaviors, including aggression. Here we show in Drosophila melanogaster that both 5-HT and neuropeptide F, the invertebrate homolog of neuropeptide Y, modulate aggression. We show that drug-induced increases of 5-HT in the fly brain increase aggression. Elevating 5-HT genetically in the serotonergic circuits recapitulates these pharmacological effects, whereas genetic silencing of these circuits makes the flies behaviorally unresponsive to the drug-induced increase of 5-HT but leaves them capable of aggression. Genetic silencing of the neuropeptide F (npf) circuit also increases fly aggression, demonstrating an opposite modulation to 5-HT. Moreover, this neuropeptide F effect seems to be independent of 5-HT. The implication of these two modulatory systems in fly and mouse aggression suggest a marked degree of conservation and a deep molecular root for this behavior.

}, keywords = {Aggression, Analysis of Variance, Animals, Behavior, Animal, Biological Evolution, Brain, Drosophila melanogaster, Drosophila Proteins, Gene Silencing, Neuropeptides, Reverse Transcriptase Polymerase Chain Reaction, Serotonin}, issn = {1061-4036}, doi = {10.1038/ng2029}, author = {Dierick, Herman A and Greenspan, Ralph J} }