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1.
Geneticists have, for years, understood the nature of genome‐wide association studies using common genomic variants. Recently, however, focus has shifted to the analysis of rare variants. This presents potential problems for researchers, as rare variants do not always behave in the same way common variants do, sometimes rendering decades of solid intuition moot. In this paper, we present examples of the differences between common and rare variants. We show why one must be significantly more careful about the origin of rare variants, and how failing to do so can lead to highly inflated type I error. We then explain how to best avoid such concerns with careful understanding and study design. Additionally, we demonstrate that a seemingly low error rate in next‐generation sequencing can dramatically impact the false‐positive rate for rare variants. This is due to the fact that rare variants are, by definition, seen infrequently, making it hard to distinguish between errors and real variants. Compounding this problem is the fact that the proportion of errors is likely to get worse, not better, with increasing sample size. One cannot simply scale their way up in order to solve this problem. Understanding these potential pitfalls is a key step in successfully identifying true associations between rare variants and diseases. 相似文献
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Introduction The associations between vitamin D receptor (VDR) Bsm I and Fok I genotypes, parity, and risk of osteoporotic hip fracture were evaluated in a statewide population-based case-control study in Utah.Methods Women age 50–89 years with hip fracture (n=882) were ascertained via surveillance of 18 Utah hospitals from 1997 to 2001. Age-matched controls were randomly selected (n=897). Participants were interviewed in their homes, and blood samples were collected for genotyping.Results In logistic regression analyses that controlled for multiple confounders, Bsm I VDR genotype but not Fok I genotype was associated with risk of osteoporotic hip fracture (OR bb vs. BB genotype: 0.68; 95% CI: 0.50, 0.95). In similar analyses, no overall association was observed between parity status and risk of osteoporotic hip fracture. However, the effect of VDR genotype was modified by parity status. Among nulliparous women (n=140), Bsm I genotype was not associated with risk of hip fracture (OR bb vs. BB: 0.82; 95% CI: 0.28, 2.4); among primiparous women (n=133), bb genotype was associated with increased risk of hip fracture (OR bb vs. BB: 3.30; 95% CI: 0.96, 11.29); among multiparous women (n=1,400), bb genotype was associated with decreased risk of hip fracture (OR bb vs. BB: 0.59; 95% CI: 0.42, 0.84).Conclusion VDR Bsm I genotype was associated with risk of hip fracture in Utah women, and this effect was modified by parity status. Hormonal or lifestyle factors related to parity may underlie this interaction. 相似文献
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Approximately one quarter of a series of 45 schizophrenic and schizoaffective patients with operationally diagnosed episodes of postpsychotic depression were also found to have anxiety symptoms consistent with the panic-attack syndrome. The incidence of such attacks was distributed across all demographic groups. Heuristic and treatment implications of this observation are considered. 相似文献
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Stefanie Sarantopoulos Kristen E Stevenson Haesook T Kim Nazmim S Bhuiya Corey S Cutler Robert J Soiffer Joseph H Antin Jerome Ritz 《Clinical cancer research》2007,13(20):6107-6114
PURPOSE: Recent studies suggest that donor B cells as well as T cells contribute to immune pathology in patients with chronic graft-versus-host disease (GVHD). B-cell activating factor (BAFF) promotes survival and differentiation of activated B cells. Thus, we tested whether BAFF correlated with chronic GVHD disease activity and time of onset after allogeneic hematopoietic stem cell transplantation (HSCT). EXPERIMENTAL DESIGN: Patients who had undergone allogeneic HSCT between 1994 and 2005 for hematologic malignancies were studied. ELISA was used to measure plasma BAFF levels and flow cytometry was used to assess BAFF receptor expression on B cells in patients with or without chronic GVHD. RESULTS: In 104 patients, BAFF levels were significantly higher in patients with active chronic GVHD compared with those without disease (P = 0.02 and 0.0004, respectively). Treatment with high-dose prednisone (>or=30 mg/d) was associated with reduced BAFF levels in patients with active chronic GVHD (P = 0.0005). Serial studies in 24 patients showed that BAFF levels were high in the first 3 months after HSCT but subsequently decreased in 13 patients who never developed chronic GVHD. In contrast, BAFF levels remained elevated in 11 patients who developed chronic GVHD. Six-month BAFF levels >or=10 ng/mL were strongly associated with subsequent development of chronic GVHD (P < 0.0001). Following transplant, plasma BAFF levels correlated inversely with BAFF receptor expression on B cells (P = 0.01), suggesting that soluble BAFF affected B cells through this receptor. CONCLUSION: These results suggest that elevated BAFF levels contribute to B-cell activation in patients with active chronic GVHD. 相似文献
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Using data from the 1984 Supplement on Aging to the National Health Interview Survey, this study examined residential differences on a selected group of health status measures among persons 65 years of age and older (N = 11,497). Mean values on indicators of health and impairment for each of the residence categories were examined before and after adjusting for distributional differences in background and demographic characteristics which are associated with both health and residence. Three important conclusions emerged from the analysis: (1) health status does not vary with residence in a unitary fashion; (2) the relationship between residence and health status does not appear to fall along a straightforward rural-urban continuum; and (3) there is both diversity in, and a general patterning of, the significant relationships between health and residence with the extremes of health status located in the rural categories. 相似文献
9.
Neuron-specific enolase (NSE), a glycolytic enzyme enolase found in brain, was examined in the cerebrospinal fluid and serum of 30 patients with presumptive Alzheimer's disease (AD) and of 13 healthy controls and evaluated as a measure of neuronal functional activity associated with AD. The cerebrospinal fluid NSE levels of patients with AD were significantly reduced and serum NSE levels were significantly increased from controls. Cerebrospinal fluid NSE levels may be representative of central nervous system cell loss or a decrease in neuronal functional activity associated with AD. 相似文献
10.
Larry R. Faulkner M.D. Joseph D. Bloom M.D. David L. Cutler M.D. James H. Shore M.D. J. Donald Bray M.D. Joseph Murray M.S. 《Community mental health journal》1987,23(4):260-270
The authors review the relationship that has evolved over the years between the Department of Psychiatry at Oregon Health Sciences University and Oregon's community and state mental health programs. They describe the compatibility that exists between the basic requirements of academic psychiatry departments and public mental health programs and demonstrate how these organizations have been able to fulfill one another's needs in Oregon. Specific examples of successful collaborations in the areas of education, administration, research, and service are presented to illustrate how relationships that have been designed to meet specific requirements of one organization can fulfill many requirements of both. Suggestions are provided for those organizations contemplating similar collaborative endeavors. 相似文献