A Powerful Approach to Sub-Phenotype Analysis in Population-Based Genetic Association Studies

The ultimate goal of genome-wide association (GWA) studies is to identify genetic variants contributing effects to complex phenotypes in order to improve our understanding of the biological architecture underlying the trait. One approach to allow us to meet this challenge is to consider more refined sub-phenotypes of disease, defined by pattern of symptoms, for example, which may be physiologically distinct, and thus may have different underlying genetic causes. The disadvantage of sub-phenotype analysis is that large disease cohorts are sub-divided into smaller case categories, thus reducing power to detect association. To address this issue, we have developed a novel test of association within a multinomial regression modeling framework, allowing for heterogeneity of genetic effects between sub-phenotypes. The modeling framework is extremely flexible, and can be generalized to any number of distinct sub-phenotypes. Simulations demonstrate the power of the multinomial regression-based analysis over existing methods when genetic effects differ between sub-phenotypes, with minimal loss of power when these effects are homogenous for the unified phenotype. Application of the multinomial regression analysis to a genome-wide association study of type 2 diabetes, with cases categorized according to body mass index, highlights previously recognized differential mechanisms underlying obese and non-obese forms of the disease, and provides evidence of a potential novel association that warrants follow-up in independent replication cohorts

Partial least square regression applied to the QTLMAS 2010 dataset

Detection of genomic regions affecting traits is a goal in many genetic studies. Studies applying distinct methods for detection of these regions, called quantitative trait loci (QTL), have been described, ranging from single marker regression [1] to methods that enable to fit several markers simultaneously [2,3]. Simultaneously fitting all markers leads to more accurate detection of QTL compared to independent fitting of single markers in a regression model when there is linkage disequilibrium (LD) between the genomic regions that affect the trait but comes at the cost of increased computational requirements [2]. Partial least square regression (PLSR) is one method for simultaneously fitting multiple markers and was applied by Bjornstad et al. for detection of QTL [3]. An interesting characteristic of PLSR its straightforward application of to simultaneous analysis of data of multiple traits [3]. The objectives of this study were to use PLSR to search for QTL and to estimate breeding values in the dataset of the QTLMAS 2010 worksho

Retrospective evaluation of foot-and-mouth disease vaccineeffectiveness in Turkey

AbstractFoot-and-mouth disease (FMD) is present in much of Turkey and its control is largely based on vaccination. The arrival of the FMD Asia-1 serotype in Turkey in 2011 caused particular concern, spreading rapidly westwards across the country towards the FMD free European Union. With no prior natural immunity, control of spread would rely heavily on vaccination.Unlike human vaccines, field protection is rarely evaluated directly for FMD vaccines. Between September 2011 and July 2012 we performed four retrospective outbreak investigations to assess the vaccine effectiveness (VE) of FMD Asia-1 vaccines in Turkey. Vaccine effectiveness is defined as the reduction in risk in vaccinated compared to unvaccinated individuals with similar virus exposure in the field.The four investigations included 12 villages and 1230 cattle >4 months of age. One investigation assessed the FMD Asia-1 Shamir vaccine, the other three evaluated the recently introduced FMD Asia-1 TUR 11 vaccine made using a field isolate of the FMD Asia-1 Sindh-08 lineage that had recently entered Turkey.After adjustment for confounding, the TUR 11 vaccine provided moderate protection against both clinical disease VE=69% [95% CI: 50%–81%] and infection VE=63% [95% CI: 29%–81%]. However, protection was variable with some herds with high vaccine coverage still experiencing high disease incidence. Some of this variability will be the result of the variation in virus challenge and immunity that occurs under field conditions.In the outbreak investigated there was no evidence that the Asia-1 Shamir vaccine provided adequate protection against clinical FMD with an incidence of 89% in single vaccinated cattle and 69% in those vaccinated two to five times.Based on these effectiveness estimates, vaccination alone is unlikely to produce the high levels of herd immunity needed to control FMD without additional control measures

Can video mobile phones improve CPR quality when used for dispatcher assistance during simulated cardiac arrest?

Denne artikkelen er en del av doktorgradsavhandlingen til Stein Roar Bolle. Avhandlingen finnes i Munin http://hdl.handle.net/10037/3597Background: Because mobile telephones may support video calls, emergency medical dispatchers may now connect visually with bystanders during pre-hospital cardiopulmonary resuscitation (CPR). We studied the quality of simulated dispatcher-assisted CPR when guidance was delivered to rescuers by video calls or audio calls from mobile phones. Methods: One hundred and eighty high school students were randomly assigned in groups of three to communicate via video calls or audio calls with experienced nurse dispatchers at a Hospital Emergency Medical Dispatch Center. CPR was performed on a recording resuscitation manikin during simulated cardiac arrest. Quality of CPR and time factors were compared depending on the type of communication used. Results: The median CPR time without chest compression (‘hands-off time’) was shorter in the video-call group vs. the audio-call group (303 vs. 331 s; P50.048), but the median time to first compression was not shorter (104 vs. 102 s; P50.29). The median time to first ventilation was insignificantly shorter in the video-call group (176 vs. 205 s; P50.16). This group also had a slightly higher proportion of ventiliations without error (0.11 vs. 0.06; P50.30). Conclusion: Video communication is unlikely to improve telephone CPR (t-CPR) significantly without proper training of dispatchers and when using dispatch protocols written for audio-only calls. Improved dispatch procedures and training for handling video calls require further investigation

Examining the transcriptional response in wheat Fhb1 near-isogenic lines to Fusarium graminearum infection and deoxynivalenol treatment

Citation: Hofstad, A. N., Nussbaumer, T., Akhunov, E., Shin, S., Kugler, K. G., Kistler, H. C., . . . Muehlbauer, G. J. (2016). Examining the transcriptional response in wheat Fhb1 near-isogenic lines to Fusarium graminearum infection and deoxynivalenol treatment. Plant Genome, 9(1). https://doi.org/10.3835/plantgenome2015.05.0032Fusarium head blight (FHB) is a disease caused predominantly by the fungal pathogen Fusarium graminearum that affects wheat and other small-grain cereals and can lead to severe yield loss and reduction in grain quality. Trichothecene mycotoxins, such as deoxynivalenol (DON), accumulate during infection and increase pathogen virulence and decrease grain quality. The Fhb1 locus on wheat chromosome 3BS confers Type II resistance to FHB and resistance to the spread of infection on the spike and has been associated with resistance to DON accumulation. To gain a better genetic understanding of the functional role of Fhb1 and resistance or susceptibility to FHB, we examined DON and ergosterol accumulation, FHB resistance, and the whole-genome transcriptomic response using RNA-seq in a near-isogenic line (NIL) pair carrying the resistant and susceptible alleles for Fhb1 during F. graminearum infection and DON treatment. Our results provide a gene expression atlas for the resistant and susceptible wheat–F. graminearum interaction. The DON concentration and transcriptomic results show that the rachis is a key location for conferring Type II resistance. In addition, the wheat transcriptome analysis revealed a set of Fhb1-responsive genes that may play a role in resistance and a set of DON-responsive genes that may play a role in trichothecene resistance. Transcriptomic results from the pathogen show that the F. graminearum genome responds differently to the host level of resistance. The results of this study extend our understanding of host and pathogen responses in the wheat–F. graminearum interaction. © Crop Science Society of America

Strain- and plasmid-level deconvolution of a synthetic metagenome by sequencing proximity ligation products

Metagenomics is a valuable tool for the study of microbial communities but has been limited by the difficulty of “binning” the resulting sequences into groups corresponding to the individual species and strains that constitute the community. Moreover, there are presently no methods to track the flow of mobile DNA elements such as plasmids through communities or to determine which of these are co-localized within the same cell. We address these limitations by applying Hi-C, a technology originally designed for the study of three-dimensional genome structure in eukaryotes, to measure the cellular co-localization of DNA sequences. We leveraged Hi-C data generated from a simple synthetic metagenome sample to accurately cluster metagenome assembly contigs into groups that contain nearly complete genomes of each species. The Hi-C data also reliably associated plasmids with the chromosomes of their host and with each other. We further demonstrated that Hi-C data provides a long-range signal of strain-specific genotypes, indicating such data may be useful for high-resolution genotyping of microbial populations. Our work demonstrates that Hi-C sequencing data provide valuable information for metagenome analyses that are not currently obtainable by other methods. This metagenomic Hi-C method could facilitate future studies of the fine-scale population structure of microbes, as well as studies of how antibiotic resistance plasmids (or other genetic elements) mobilize in microbial communities. The method is not limited to microbiology; the genetic architecture of other heterogeneous populations of cells could also be studied with this technique

Evaluation and Comparison of a Habitat Suitability Model for Postdrift Larval Lake Sturgeon in the St. Clair and Detroit Rivers

We evaluated composition and spatial distribution of riverine nursery habitat for larval Lake Sturgeon Acipenser fulvescens in the Middle Channel of the St. Clair River, Michigan, and Fighting Island Channel of the Detroit River, Ontario, using a habitat suitability model (HSM) and fish collections. Although model outputs indicated similar portions of high‐quality habitat in the Middle Channel (16.9%) and Fighting Island Channel (15.7%), larval abundance and dispersal patterns varied between these systems. Analysis with Akaike’s information criterion indicated that a regression model using sand–silt substrate performed best at predicting the observed water‐volume‐standardized CPUE (number of larvae·h−1·m−3) in the Middle Channel. Of 93 larvae that were collected in the Middle Channel, most were found to cluster at three distinct areas of high‐ and moderate‐quality habitat, which was composed predominately of sand–silt substrate. Lengths of larvae varied by as much as 9 mm, and the degree of yolk sac absorption also varied, indicating that larvae in the Middle Channel remained within the channel after a short drift downstream. Of the 25 larvae that were collected in Fighting Island Channel, distribution was sporadic, and occurrence did not significantly correlate with measured habitat variables. Larvae were relatively homogeneous in size and yolk sac stage, indicating that newly emerged larvae did not utilize available habitat in Fighting Island Channel but instead drifted into the main channel of the Detroit River. Dispersal patterns indicate variability in young Lake Sturgeon ecology, which is dependent on local habitat conditions—most notably, substrate composition. Furthermore, modeled larval–habitat associations found in this study were compared to a similar study on larval Lake Sturgeon from the North Channel of the St. Clair River. Model outputs from all three systems accurately accounted for observed larval dispersal patterns among both rivers. This supports the transferability of an HSM parameterized for Lake Sturgeon from individual river reaches within two large river systems.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146299/1/nafm10217.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146299/2/nafm10217_am.pd

Comparison of the National Early Warning Score in non-elective medical and surgical patients.

BACKGROUND: The National Early Warning Score (NEWS) is used to identify deteriorating patients in hospital. NEWS is a better discriminator of outcomes than other early warning scores in acute medical admissions, but it has not been evaluated in a surgical population. The study aims were to evaluate the ability of NEWS to discriminate cardiac arrest, death and unanticipated ICU admission in patients admitted to surgical specialties, and to compare the performance of NEWS in admissions to medical and surgical specialties. METHODS: Hospitalwide data over 31 months, from adult inpatients who stayed at least one night or died on the day of admission, were analysed. The data were categorized as elective or non-elective surgical or medical admissions. The ability of NEWS to discriminate the outcomes above in these different groups was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: There were too few outcomes to permit meaningful comparison of elective admissions, so the analysis was constrained to comparison of non-elective admissions. NEWS performed equally well, or better, for surgical as for medical patients. For death within 24 h the AUROC for surgical admissions was 0·914 (95 per cent c.i. 0·907 to 0·922), compared with 0·902 (0·898 to 0·905) for medical admissions. For the combined outcome of any of death, cardiac arrest or unanticipated ICU admission, the AUROC was 0·874 (0·868 to 0·880) for surgical admissions and 0·874 (0·871 to 0·877) for medical admissions. CONCLUSION: NEWS discriminated deterioration in non-elective surgical patients at least as well as in non-elective medical patients