Rare Variants in Ischemic Stroke: An Exome Pilot Study

The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined

Diffusion of Innovation: State Factors that Influence the Spread of School Based Mental Health Policies and Programs

A number of trends in adolescent health have increased the importance of mental health services. In 1999, there were about 21 percent of children and adolescents between the ages of 9 and 17 that had a diagnosable mental disorder, causing some functional impairment (US DHHS, 1999). School based mental health (SBMH) has been reported to increase access to services (Armbruster, Gerstein & Fallon, 1997, Weist & Albus, 2004). Seventy-five percent of children who have mental health problems do not receive care (Kataoka, Zhang & Wells, 2002). Of those that receive care, 75 percent receive care from within the school (Burns, et al, 1995). ""SBMH services offer promise in the effort to bridge the gap between service need and service utilization by providing access to underserved populations""(Armbruster & Lichtman, 1999, p.493). However, states vary in their ability to provide services to children in school based mental health settings. This study conducted interviews with participants in nine states that are establishing connections between schools and mental health systems. Information gathered from these states was then used to seek opinions and perceptions of other State Mental Health Directors for Children. The model for this study combined the works of Rogers (1995), Berry and Berry (1990) and Mintrom and Vergari (1998) to examine the factors that influence the diffusion of innovation. The qualitative piece of this research identifies prominent necessities in an innovative SBMH program, factors that facilitate SBMH programs and barriers to innovative SBMH programs. The questionnaires that were sent to each of the state Directors also provided data on perceptions of SBMH innovations. The multivariate analyses included twenty programmatic measures and two per capita spending measures of readiness for innovation in SBMH. The models that were estimated revealed that state resources matter. The professionalism measure also showed a positive association. Bivariate analyses between measures of innovation and Census Divisions revealed some positive associations. The political variables did not show any associations with measures of readiness for innovation in the models

Diffusion of Innovation: State Factors that Influence the Spread of School Based Mental Health Policies and Programs

A number of trends in adolescent health have increased the importance of mental health services. In 1999, there were about 21 percent of children and adolescents between the ages of 9 and 17 that had a diagnosable mental disorder, causing some functional impairment (US DHHS, 1999). School based mental health (SBMH) has been reported to increase access to services (Armbruster, Gerstein & Fallon, 1997, Weist & Albus, 2004). Seventy-five percent of children who have mental health problems do not receive care (Kataoka, Zhang & Wells, 2002). Of those that receive care, 75 percent receive care from within the school (Burns, et al, 1995). ""SBMH services offer promise in the effort to bridge the gap between service need and service utilization by providing access to underserved populations""(Armbruster & Lichtman, 1999, p.493). However, states vary in their ability to provide services to children in school based mental health settings. This study conducted interviews with participants in nine states that are establishing connections between schools and mental health systems. Information gathered from these states was then used to seek opinions and perceptions of other State Mental Health Directors for Children. The model for this study combined the works of Rogers (1995), Berry and Berry (1990) and Mintrom and Vergari (1998) to examine the factors that influence the diffusion of innovation. The qualitative piece of this research identifies prominent necessities in an innovative SBMH program, factors that facilitate SBMH programs and barriers to innovative SBMH programs. The questionnaires that were sent to each of the state Directors also provided data on perceptions of SBMH innovations. The multivariate analyses included twenty programmatic measures and two per capita spending measures of readiness for innovation in SBMH. The models that were estimated revealed that state resources matter. The professionalism measure also showed a positive association. Bivariate analyses between measures of innovation and Census Divisions revealed some positive associations. The political variables did not show any associations with measures of readiness for innovation in the models

Select Gene Analyses: 10 Exome Cases vs. 3 Control Populations.

<p>Select Gene Analyses: 10 Exome Cases vs. 3 Control Populations.</p

SNPs in the 10 cases exomes vs. 3 control populations.

<p>SNPs in the 10 cases exomes vs. 3 control populations.</p

Summary of the pipeline steps.

<p>Summary of the pipeline steps.</p

GEOS population characteristics by case-control status.

<p>GEOS population characteristics by case-control status.</p

Sequencing and Alignment Statistics for Ten Stroke Exomes.

<p>Sequencing and Alignment Statistics for Ten Stroke Exomes.</p

Characteristics of the 10 male stroke cases implemented in the pilot study.

<p>Characteristics of the 10 male stroke cases implemented in the pilot study.</p

Compound heterozygotes in exome data for genes in which every case had a least two novel variants in the same gene isoform, only 6 genes (9 total isoforms) satisfied this criterion.

<p>The figure illustrates the 9 isoforms (left y-axis) per sample (x-axis) by variant type (left y-axis). Notably, two of the <i>CTPB2</i> isoforms (NM_001329 and NM_ 001083914) were seen to have a non-sense codon occurring in all 10 samples.</p