Nonsampling errors and their implication for estimates of current cancer treatment using the Medical Expenditure Panel Survey

Survey nonsampling errors refer to the components of total survey error (TSE) that result from failures in data collection and processing procedures. Evaluating nonsampling errors can lead to a better understanding of their sources, which in turn, can inform survey inference and assist in the design of future surveys. Data collected via supplemental questionnaires can provide a means for evaluating nonsampling errors because it may provide additional information on survey nonrespondents and/or measurements of the same concept over repeated trials on the same sampling unit. We used a supplemental questionnaire administered to cancer survivors to explore potential nonsampling errors, focusing primarily on nonresponse and measurement/specification errors. We discuss the implications of our findings in the context of the TSE paradigm and identify areas for future research

Detectable Clonal Mosaicism from Birth to Old Age and its Relationship to Cancer

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18)

Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10-6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. © 2014 Plenge et al

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Politics and Public Education in the Great Depression: Detroit, 1929-1940 (Urban Schools; Michigan).

The Great Depression profoundly influenced the history and politics of public education in Detroit. Specifically, the Depression affected the alignments in educational politics due to battles about retrenchment and revenue, the civil liberties of teachers, the function of high schools, and the high school curriculum. In the budget controversies, conservatives and business leaders called for severe retrenchment, while liberals and organized labor fought to hold the line on cutbacks. School leaders initially resisted budget reductions but finally were forced by the city's bankers to reduce expenses. Teachers' salaries were slashed but no teachers were fired. No programs were cut in spite of conservative and business agitation for elimination of "fads and frills." School leaders removed the traditional restraints on political activity by teachers in order to get their help in the retrenchment controversies. By 1934 teachers were involved in every phase of educational politics. Conservatives and business leaders opposed such activities, particularly when teachers and administrators worked for new tax levies to increase state support for public education. Some teachers further outraged the conservative community by campaigning to unseat several school board members. The Board of Education took no reprisals against those teachers and throughout the decade, remained committed to civil liberties. Despite agitation about radical teachers from such groups as the American Legion, and accusations of Communist subversion in the Detroit schools by witnesses before the Dies Committee, the board took no action against politically active teachers. A staunchly left-wing teachers union grew during these years and played an active role in educational politics. Finally, Detroit's young people were particularly hard hit by the Depression as employment prospects for them almost disappeared. High school enrollments soared. Detroit's school leaders "watered-down" high school curricula because they believed these young people were less able than previous waves of students. Competition between the National Youth Administration and educators' belief that the high school should be the primary agency for dealing with youth also influenced the curriculum revisions. The 1930's hastened the shift of the high school from a vocational to a custodial institution.Ph.D.Education historyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160388/1/8502895.pd