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230
Genomic control for association studies
, 1999
"... A dense set of single nucleotide polymorphisms (SNP) covering the genome and an efficient method to assess SNP genotypes are expected to be available in the near future. An outstanding question is how to use these technologies efficiently to identify genes affecting liability to complex disorders. ..."
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Cited by 480 (13 self)
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A dense set of single nucleotide polymorphisms (SNP) covering the genome and an efficient method to assess SNP genotypes are expected to be available in the near future. An outstanding question is how to use these technologies efficiently to identify genes affecting liability to complex disorders. To achieve this goal, we propose a statistical method that has several optimal properties: It can be used with casecontrol data and yet, like family-based designs, controls for population heterogeneity; it is insensitive to the usual violations of model assumptions, such as cases failing to be strictly independent; and, by using Bayesian outlier methods, it circumvents the need for Bonferroni correction for multiple tests, leading to better performance in many settings while still constraining risk for false positives. The performance of our genomic control method is quite good for plausible effects of liability genes, which bodes well for future genetic analyses of complex disorders.
J: Power and sample size calculations for case-control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum Hered 2002
"... disequilibrium W Non-centrality parameter The purpose of this work is to quantify the effects that errors in genotyping have on power and the sample size necessary to maintain constant asymptotic Type I and Type II error rates (SSN) for case-control genetic association studies between a disease phen ..."
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Cited by 61 (10 self)
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disequilibrium W Non-centrality parameter The purpose of this work is to quantify the effects that errors in genotyping have on power and the sample size necessary to maintain constant asymptotic Type I and Type II error rates (SSN) for case-control genetic association studies between a disease phenotype and a di-allelic marker locus, for example a single nucleotide polymorphism (SNP) locus. We consider the effects of three published models of genotyping errors on the chi-square test for independence in the 2! 3 table. After specifying genotype frequencies for the marker locus conditional on disease status and error model in both a genetic model-based and a genetic model-free framework, we compute the asymptotic power to detect association through
Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Infect. Immun. 70, 204–210 (erratum in: Infect
- Immun
, 2002
"... Colonization of the gastrointestinal tract with vancomycin-resistant Enterococcus faecium (VRE) has become endemic in many hospitals and nursing homes in the United States. Such colonization predisposes the individual to VRE bacteremia and/or endocarditis, and immunocompromised patients are at parti ..."
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Cited by 43 (1 self)
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Colonization of the gastrointestinal tract with vancomycin-resistant Enterococcus faecium (VRE) has become endemic in many hospitals and nursing homes in the United States. Such colonization predisposes the individual to VRE bacteremia and/or endocarditis, and immunocompromised patients are at particular risk for these conditions. The emergence of antibiotic-resistant bacterial strains requires the exploration of alternative antibacterial therapies, which led our group to study the ability of bacterial viruses (bacteriophages, or phages) to rescue mice with VRE bacteremia. The phage strain used in this study has lytic activity against a wide range of clinical isolates of VRE. One of these VRE strains was used to induce bacteremia in mice by intraperitoneal (i.p.) injection of 109 CFU. The resulting bacteremia was fatal within 48 h. A single i.p. injection of 3 108 PFU of the phage strain, administered 45 min after the bacterial challenge, was sufficient to rescue 100 % of the animals. Even when treatment was delayed to the point where all animals were moribund, approximately 50% of them were rescued by a single injection of this phage preparation. The ability of this phage to rescue bacteremic mice was demonstrated to be due to the functional capabilities of the phage and not to a nonspecific immune effect. The rescue of bacteremic mice could be effected only by phage strains able to grow in vitro on the bacterial host used to infect the animals, and when such strains are heat inactivated they lose their ability to rescue the infected mice. Isolates of vancomycin-resistant Enterococcus faecium
Honest variable selection in linear and logistic regression models via ℓ1 and ℓ1 +ℓ2 penalization
- Electronic Journal of Statistics
"... This paper investigates correct variable selection in finite samples via ℓ1 and ℓ1+ℓ2 type penalization schemes. The asymptotic consistency of variable selection immediately follows from this analysis. We focus on logistic and linear regression models. The following questions are central to our pape ..."
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Cited by 39 (3 self)
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This paper investigates correct variable selection in finite samples via ℓ1 and ℓ1+ℓ2 type penalization schemes. The asymptotic consistency of variable selection immediately follows from this analysis. We focus on logistic and linear regression models. The following questions are central to our paper: given
Learning Your Identity and Disease from Research Papers: Information Leaks in Genome Wide Association Study
"... Genome-wide association studies (GWAS) aim at discovering the association between genetic variations, particularly single-nucleotide polymorphism (SNP), and common diseases, which have been well recognized to be one of the most important and active areas in biomedical research. Also renowned is the ..."
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Cited by 35 (3 self)
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Genome-wide association studies (GWAS) aim at discovering the association between genetic variations, particularly single-nucleotide polymorphism (SNP), and common diseases, which have been well recognized to be one of the most important and active areas in biomedical research. Also renowned is the privacy implication of such studies, which has been brought into the limelight by the recent attack proposed by Homer et al. Homer’s attack demonstrates that it is possible to identify a participant of a GWAS from analyzing the allele frequencies of a large number of SNPs. Such a threat, unfortunately, was found in our research to be significantly understated. In this paper, we demonstrate that individuals can actually be identified from even a relatively small set of statistics, as those routinely published in GWAS papers. We present two attacks. The first one extends Homer’s attack with a much more powerful test statistic, based on the correlations among different SNPs described by coefficient of determination (r 2). This attack can determine the presence of an individual in a GWAS from the statistics related to a couple of hundred SNPs. The second attack can lead to complete disclosure of hundreds of the participants ’ SNPs, by analyzing the information derived from the published statistics. We also found that those attacks can succeed even when the precisions of the statistics are low and part of data is missing, which makes the effects of such simple defense limited. We evaluated our attacks on the real human genomes from the International HapMap project, and concluded that such threats are completely realistic.
Investigating non-response bias in mail surveys
- J. Epidemiol. Community Health
, 1981
"... SUMMARY Losses in follow-up that are biased with respect to outcome invalidate the results. There are many ways of dealing with non-response in follow-up studies. Three separate methods were used to investigate a potential bias in a mail survey of 2471 disabled people. At a response rate of 84%, the ..."
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Cited by 29 (0 self)
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SUMMARY Losses in follow-up that are biased with respect to outcome invalidate the results. There are many ways of dealing with non-response in follow-up studies. Three separate methods were used to investigate a potential bias in a mail survey of 2471 disabled people. At a response rate of 84%, the non-respondents were significantly different from the respondents with respect to the outcome, return to work and vocational training. The success rate in terms of the outcome was negatively related to the number of reminders. Significant differences were found in response rates according to age, social class, impairments, previous employment record, and completion of rehabilitation courses. There is no safe level of response rates below 100%. However small the non-response, a possible bias as a result of it must be investigated. In spite of all the forethought and persistence put into follow-up, there are almost always some unco-operative individuals who fail to respond. Whatever the cause, non-respondents may not be a random subgroup, that is, the respondents may not be representative of the parent population.
Breast cancer in women after repeated fluoroscopic examinations of the chest
- J Natl Cancer Inst
"... ABSTRACT-A follow·up study of 1,764 female patients, discharged alive from two tuberculosis sanatoria in Mas· sachusetts between 1930 and 1954, was conducted. In the course of air collapse therapy of the lung (pneumothorax and pneumoperitoneum), 1,047 women were fluoroscopically exam· ined an averag ..."
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Cited by 22 (0 self)
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ABSTRACT-A follow·up study of 1,764 female patients, discharged alive from two tuberculosis sanatoria in Mas· sachusetts between 1930 and 1954, was conducted. In the course of air collapse therapy of the lung (pneumothorax and pneumoperitoneum), 1,047 women were fluoroscopically exam· ined an average of 102 times over a period of several years. A comparison group of 717 women with tuberculosis received other treatments that did not require fluoroscopic monitoring. A 1975 mailing address or a death certificate was obtained for 93.6 % of the study subjects, and 78 % of 1,146 living patients responded to a mailed questionnaire. An excess of breast cancer (41 observed and 23.3 expected) was seen among the fluoroscopically exam· ined women, whereas no excess (15 observed and 14.1 expected) was apparent among the comparison women. When age was con· sidered, the greatest absolute excess breast cancer risk occurred
J: Confounding from cryptic relatedness in case-control association studies. Plos Genet
, 2005
"... Case-control association studies are widely used in the search for genetic variants that contribute to human diseases. It has long been known that such studies may suffer from high rates of false positives if there is unrecognized population structure. It is perhaps less widely appreciated that so-c ..."
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Cited by 18 (0 self)
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Case-control association studies are widely used in the search for genetic variants that contribute to human diseases. It has long been known that such studies may suffer from high rates of false positives if there is unrecognized population structure. It is perhaps less widely appreciated that so-called ‘‘cryptic relatedness’ ’ (i.e., kinship among the cases or controls that is not known to the investigator) might also potentially inflate the false positive rate. Until now there has been little work to assess how serious this problem is likely to be in practice. In this paper, we develop a formal model of cryptic relatedness, and study its impact on association studies. We provide simple expressions that predict the extent of confounding due to cryptic relatedness. Surprisingly, these expressions are functions of directly observable parameters. Our analytical results show that, for well-designed studies in outbred populations, the degree of confounding due to cryptic relatedness will usually be negligible. However, in contrast, studies where there is a sampling bias toward collecting relatives may indeed suffer from excessive rates of false positives. Furthermore, cryptic relatedness may be a serious concern in founder populations that have grown rapidly and recently from a small size. As an example, we analyze the impact of excess relatedness among cases for six phenotypes measured in the Hutterite population. Citation: Voight BF, Pritchard JK (2005) Confounding from cryptic relatedness in case-control association studies. PLoS Genet 1(3): e32.
