7 research outputs found
The Evolving Role of the U.S. Office of Management and Budget in Regulatory Policy
No full textSince the early Reagan years, critics have argued that benefit-cost analysis is used by the U.S. Office of Management and Budget (OMB) as a one-sided tool of deregulation to advance the interests of business. This article discloses a little-known fact: OMB also plays a powerful pro-regulation role when agency proposals address market failures and are supported by benefit-cost analysis. Drawing on four case studies from the George W. Bush Administration, the author examines how and why OMB encouraged regulatory initiatives while protecting some rulemakings from opposition by forces inside and outside of the executive branch. The case studies address the labeling of foods for trans fat content, control of diesel engine exhaust, improvement of light-truck fuel economy, and control of air pollution from coal-fired power plants. OMB's role in the 2001-2006 period was unusual by historic standards because, rather than await agency drafts, OMB played a pro-active role in both the initiation of rulemakings and the creation of regulatory alternatives for consideration. The benefit-cost framework could be much more powerful if greater investments were made in applied research to expand knowledge on key regulatory issues.
Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index
No full textThe phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ~4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity. © 2014 Hoggart et al
Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
No full textThe phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to>56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ~4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity
Explanation of the POE test.
No full text<p>Top panel illustrates the phenotype distributions in the four genotype groups that would be observed if the parent-of-origin of the alleles were known. Bottom panel shows how these distributions change if the parent-of-origin is unobserved. The resulting heterozygous group will have increased variance due to its heterogeneity. This example describes a scenario we observe for the two replicated hits, namely that the paternal- and maternal effects are of the same size, but opposite in direction (). Therefore the average phenotype in the B/B group is the same as in the A/A group, as the paternal and maternal B allele effects cancel each other out. In the A/B group there are two subpopulations: the A-pat/B-mat group with phenotypic mean of and the A-mat/B-pat group with mean. Thus, the two subpopulations combined also have zero mean, but increased variance.</p
Discovery POE association results for the six SNPs selected for replication.
No full text<p>SNP matching any of the following two selection criteria were retained: (1) All lead SNPs with POE P-value below 5×10<sup>−6</sup>. (2) All lead SNPs falling in previously reported imprinted regions with POE P-value <5×10<sup>−4</sup>. Note that one SNP is listed twice as it met both criteria. Chr: chromosome, Gene: nearest gene, MAF: minor allele frequency, N (AA+BB): homozygous sample size, N (AB): heterozygous sample size, P-value (main): main effect association P-value in Speliotes <i>et al</i>. <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004508#pgen.1004508-Speliotes1" target="_blank">[10]</a>. The parent of origin P-value, “P-value (POE)”, is the Brown-Forsythe test P-value. SNPs marked in bold are those which replicated in the family studies, see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004508#pgen-1004508-t002" target="_blank">Table 2</a>.</p
Local association plots.
No full text<p>Panels show the local POE association P-values for the <i>KCNK9</i> (left panel) and <i>SLC2A10</i> (right panel) loci.</p
Replication of the 6 discovery SNPs in trios (or parent-offspring pairs).
No full text<p>For each target SNP, in each family we searched for trios (or parent-offspring pairs) with heterozygous offspring and determined the parent of origin of the alleles (whenever possible). From each family at most one heterozygous offspring with known parental origin was then collected and grouped according to the parental origin of the alleles. The equality of phenotypic means in the two groups was tested using a Student t-test (“P-value for beta difference column”). The difference between the phenotypic means were meta-analysed using inverse-variance weighting. Table notations: “beta meta” and “P meta”: meta-analysis estimate of beta (coded paternal) - beta (coded maternal) effect size differences and the corresponding P-value, “N meta”: total number of heterozygous offspring with (coded-maternal/other-paternal), (coded-paternal/other-maternal) genotypes, respectively.</p
