Development of a discrete event simulation model for evaluating strategies of red blood cell provision following mass casualty events

Timely and adequate provision of blood following mass casualty events (MCEs) is critical to reducing mortality rates amongst casualties transported to hospital following an event. Developing planning strategies to ensure the blood transfusion demands of casualties are met is challenging. Discrete event simulation (DES) offers a novel solution to this problem which is financially efficient, less disruptive to services and allows for rich experimentation compared to the current industry standards of live exercises, round-table discussion or tabletop planning. There are currently no published models of this type for investigating blood provision in MCEs. The objective of this study was to develop a working model which could be used to target the in-hospital 'levers' and 'supply levels' of the transfusion system and improve outcomes during the response to future events. This was achieved through the robust design of a DES model using exclusive access to qualitative and quantitative data as well as a panel of experts from the field of transfusion and MCE management. The completed model was extensively and formally evaluated with secondary data from the 7th of July 2005 London bombings, the largest UK based civilian MCE in over 50 years. A subsequent sensitivity analysis revealed the five factors displaying the greatest influence on casualty outcomes. Experimental themes based on these findings have generated new solutions for managing future events which have since been presented to MCE stakeholders and policy makers

Risk for Infection with Highly Pathogenic Influenza A Virus (H5N1) in Chickens, Hong Kong, 2002

Infection was spread to commercial poultry farms through retail marking of live birds

Northern Australia beef fertility project: Cash Cow

The causes of poor reproductive performance in northern Australian beef herds are multi-factorial and uantification of the impact of individual factors on performance of breeding mobs is lacking. The reproductive performance of ~78,000 cows managed in 142 breeding mobs located on 72 commercial beef cattle properties was measured over three to four consecutive years (2008-11) using a crush-side electronic data capture system. Percentage of lactating cows pregnant within four months of calving, annual pregnancy rate, percentage foetal/calf loss between pregnancy diagnosis and weaning, and annual percentage of pregnant cows missing (mortality) were used to define performance, with the commercially achievable level of performance proposed as the performance of the 75th percentile mob or cow for each measure. Also, methods of estimating liveweight production from breeding herds were developed, and an achievable level determined for each country type. The impacts of 83 property, environmental, nutritional, management, and infectious disease factors on performance were investigated. The major factors affecting performance included country type, time of previous calving, wet season phosphorous status, cow body condition, hip-height, cow age class, cow reproductive history, severity of environmental conditions, and occurrence of mustering events around the time of calving. Producer/manager opinion that wild dogs were a problem, evidence of recent pestivirus infection and vibriosis were factors that did not contribute to the final model, but did significantly affect animal performance when present. A framework was developed for conducting economic analyses to assess the impact of factors affecting performance

Clinical evidence framework for Bayesian networks

There is poor uptake of prognostic decision support models by clinicians regardless of their accuracy. There is evidence that this results from doubts about the basis of the model as the evidence behind clinical models is often not clear to anyone other than their developers. In this paper, we propose a framework for representing the evidence-base of a Bayesian network (BN) decision support model. The aim of this evidence framework is to be able to present all the clinical evidence alongside the BN itself. The evidence framework is capable of presenting supporting and conflicting evidence, and evidence associated with relevant but excluded factors. It also allows the completeness of the evidence to be queried. We illustrate this framework using a BN that has been previously developed to predict acute traumatic coagulopathy, a potentially fatal disorder of blood clotting, at early stages of trauma care

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition