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'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'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.

Our theoretical findings on instability of Faraday waves at megahertz (MHz) drive frequency and realization of silicon-based MHz multiple-Fourier horn ultrasonic nozzles (MFHUNs) together have enabled generation of mono-disperse droplets of controllable diameter (2.5-6.0 μm) at very low electrical drive power (<0.5 Watt). The resulting battery-run clogging-free droplet generator has imminent application to pulmonary (inhalation) drug delivery and other potential applications. Here an update of advances on analysis and design of the MHz MFHUNs and the underlying physical mechanism for generation of mono-disperse micro droplets, and the nebulizer platform for application to detoxification of cyanide poisoning are presented.

An in-depth review on a new ultrasonic micro-droplet generator which utilizes megahertz (MHz) Faraday waves excited by silicon-based multiple Fourier horn ultrasonic nozzles (MFHUNs) and its potential applications is presented. The new droplet generator has demonstrated capability for producing micro droplets of controllable size and size distribution and desirable throughput at very low electrical drive power. For comparison, the serious deficiencies of current commercial droplet generators (nebulizers) and the other ultrasonic droplet generators explored in recent years are first discussed. The architecture, working principle, simulation, and design of the multiple Fourier horns (MFH) in resonance aimed at the amplified longitudinal vibration amplitude on the end face of nozzle tip, and the fabrication and characterization of the nozzles are then described in detail. Subsequently, a linear theory on the temporal instability of Faraday waves on a liquid layer resting on the planar end face of the MFHUN and the detailed experimental verifications are presented. The linear theory serves to elucidate the dynamics of droplet ejection from the free liquid surface and predict the vibration amplitude onset threshold for droplet ejection and the droplet diameters. A battery-run pocket-size clogging-free integrated micro droplet generator realized using the MFHUN is then described. The subsequent report on the successful nebulization of a variety of commercial pulmonary medicines against common diseases and on the experimental antidote solutions to cyanide poisoning using the new droplet generator serves to support its imminent application to inhalation drug delivery.

Detoxification of massive cyanide (CN) poisoning by inhalation of antidotes is recognized to be superior to intra venous (IV) or intra muscular (IM) treatment with regard to ease of administration, self-administration, and rapidity of onset. However, there are currently no effective, portable, high-throughput inhalers that can be produced in large quantities and distributed for such purpose. A hand-held inhaler has been realized using silicon-based ultrasonic nozzle to produce high-throughput of monodisperse cobinamide antidote solution for detoxification of CN poisoning in a rabbit model. © 2012 IEEE.