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Results for “genetic test utilization”

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At least 307 records · Page 17Linked to original sources

PubMed1989

[Utilization of genotoxicity tests for biological surveillance of personnel exposure].

Monitoring of those staff exposed to products or atmospheres containing carcinogenic substances may be carried out using genetic toxicology tests. These tests may highlight primary DNA modifications, genetic or chromosomal mutations, detect mutagens at the urinary level or assess a global effect, expressed by a genotoxic effect. All these tests must be used taking into account exposure kinetics, the substance in question and exposure conditions.

Humans↗

PubMed2000

The conserved PI3'K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila.

Akt (or PKB) is an oncogene involved in the regulation of cell survival. Akt is regulated by phosphatidylinositol 3-OH kinase (PI3'K) signaling and has shown to be hyperactivated through the loss of the PTEN tumor suppressor. In Drosophila, insulin signaling as studied using the Drosophila IRS-4 homolog (Chico) has been shown to be a crucial regulator of cell size. We have studied Drosophila Akt (Dakt1) and have shown that it is also involved in the regulation of cell size. Furthermore we have performed genetic epistasis tests to demonstrate that in Drosophila, PI3'K, PTEN and Akt comprise a signaling cassette that is utilized during multiple stages of development. In addition, we show that this signaling cassette is also involved in the regulation of cell survival during embryogenesis. This study therefore establishes the evolutionary conservation of this signaling pathway in Drosophila. Oncogene (2000) 19, 3971 - 3977.

Animals↗

PubMed1995

Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11 beta-hydroxysteroid dehydrogenase.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to inactive products and is thus thought to confer specificity for aldosterone on the type I mineralocorticoid receptor in the kidney. Recent studies indicate the presence of at least two isozymes of 11 beta HSD. In vitro, the NAD(+)-dependent kidney (type 2) isozyme catalyzes 11 beta-dehydrogenase but not reductase reactions, whereas the NADP(+)-dependent liver (type 1) isozyme catalyzes both reactions. We have now characterized the human gene encoding kidney 11 beta HSD (HSD11K). A bacteriophage P1 clone was isolated after screening a human genomic library by hybridization with sheep HSD11K cDNA. The gene consists of 5 exons spread over 6 kb. The nucleotide binding domain lies in the first and the second exon, and the catalytic domain in the fourth exon. The 5' flanking sequences and first exon are GC-rich (80%), suggesting that the gene may be transcriptionally regulated by factors that recognize GC-rich sequences. Fluorescence in situ hybridization of metaphase chromosomes with a positive P1 clone localized the gene to chromosome 16q22. In contrast, the HSD11L (liver isozyme) gene is located on chromosome 1 and contains 6 exons; the coding sequences of these genes are only 21% identical. HSD11K is expressed at high levels in the placenta and kidney of midgestation human fetuses and at lower levels in lung and testes. Different transcriptional start sites are utilized in kidney and placenta. These data should be applicable to genetic analysis of the syndrome of apparent mineralocorticoid excess, which may represent a deficiency of 11 beta HSD.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2005

Deficits in inhibition and flexibility are associated with the APOE-E4 allele in nondemented older adults.

This prospective study of nondemented older adults at genetic risk for AD and other types of dementia (i.e., APOE e4 allele) utilized a new Stroop test that includes a dual executive-function condition requiring both response inhibition and cognitive switching. Results indicated that, relative to non-e4 subjects, the e4 group committed more errors, but only on the new Inhibition/Switching condition. In addition, error-rate variance on this task was more heterogeneous for the e4 compared to the non-e4 group, and errors rates correlated significantly with global cognitive status (i.e., DRS scores) for the e4 group but not for the non-e4 group. These findings suggest that vulnerability to errors in response inhibition and cognitive flexibility is present in persons at risk for AD and may signal early emergence of executive dysfunction in preclinical AD. The association between these subtle executive-function deficits and the overall cognitive functioning of at-risk individuals provides further evidence of their utility as a possible preclinical marker of AD.

Aged↗

PubMed1985

Total deletion of yeast LEU4: further evidence for a second alpha-isopropylmalate synthase and evidence for tight LEU4-MET4 linkage.

Using a combination of restriction endonuclease digestion, nuclease BAL 31 treatment, and standard ligation procedures, a 4.4-kb DNA segment that carried the yeast LEU4 gene [encoding alpha-isopropylmalate synthase (IPMS) I] and adjoining sequences was excised from an appropriate plasmid and replaced with the yeast HIS3 gene. The new plasmid was digested to obtain a linear HIS3-carrying fragment flanked by remnants of the LEU4 region. Integrative transformation of a LEU4fbr LEU5+ his3- strain with this fragment resulted in the deletion of the LEU4 gene from the genome of some recipients, as demonstrated by transformant phenotype, genetic analysis and the absence of RNA capable of hybridizing to a LEU4 probe. The leu4 deletion strains remained Leu+. The extract of one such strain contained about 18% of the IPMS activity of wild-type cells. It is concluded that the residual activity is that of a second IPMS (IPMS II) that depends on an intact LEU5 locus. IPMS II was inhibited by leucine, but its sensitivity was about an order of magnitude lower than that of IPMS I. Deletion of the LEU4 region by the method utilized here resulted in an amino acid auxotrophy that could be satisfied by methionine, homocysteine, or cysteine. Complementation tests and genetic analysis demonstrated that the affected gene was MET4. Linkage to MET4 would place the LEU4 gene on the left arm of chromosome XIV.

2-Isopropylmalate Synthase↗

PubMed1999

A multiplicative-epistatic model for analyzing interspecific differences in outcrossing species.

Epistasis may play an important role in evolution and speciation. Under multiplicative interactions between different loci, an analytical model is proposed to estimate genetic parameters at the individual locus level that contribute to interspecific differences in outcrossing species. The multiplicative epistasis model, inferred from a number of animal and plant experiments, suggests that genotypes at a pair of loci have genotypic values equal to the product of genotypic values at the two different loci. By considering the genetic property of outcrossing species (i.e., high polymorphisms) in the multilevel family structure analysis for an intra- and interspecific factorial mating design, a method is developed to provide estimates for allele frequencies and additive and dominant effects at individual loci in each of the two parental populations, the genotypic values of newly formed heterozygotes through species combination each with one allele from a parental population and the second from the other parental population, and the numbers of genetic factors that lead to species differentiation. Use of clones offers a tremendous power to test the adequacy of the model. However, the utilization of the model with species that cannot be cloned is also discussed. An example with interspecific hybrids of two forest tree species is used to demonstrate the model.

Alleles↗

PubMed1980

Immune response to acute virus infection in the Syrian hamster. I. Studies on genetic restriction of cell-mediated cytotoxicity.

Syrian hamsters show evidence of classical T-cell-mediated immune reactivity to acute virus infection as judged by primary foot pad swelling, kinetics of in vitro cytotoxic activity, and virus specificity of cytotoxic effector cells. In spite of this, no evidence of genetic restriction is observed among the variety of allodisparate inbred strains tested. This virus-induced, cell-mediated killing extends across strain barriers despite strong cellular and serologic alloreactivity among some of the strains utilized. To account for the apparent lack of genetic restriction, we currently favor the hypothesis that all hamsters examined thus far share at least one class I MHC antigen. Since these animals differ at hamster loci which elicit MLR, GVHR, acute SGR, CML, and alloantibody, we presume class II MHC polymorphism exists in this species. The presence of putative class II MHC polymorphism without detectable class I polymorphism is unusual among mammals examined to date, and of unknown biologic significance.

Acute Disease↗

PubMed1975

Methionine biosynthesis in Saccharomyces cerevisiae. I. Genetical analysis of auxotrophic mutants.

In order to analyse how many structural genes are implicated in the specific steps of the biosynthesis of methionine in Sacch. cerevisiae, a hundred mutants were studied by complementation. 21 groups were defined named MET1 to MET25. Neither recombination between independent mutants of the same complementation group nor linkage between different groups was found. Preliminary to biochemical studies, mutants of each complementation group were tested for their capacity to utilize various precursors of methionine.

Genes↗

PubMed1997

Activation of the lac repressor in the transgenic mouse.

We have introduced sequences encoding the lac repressor of Escherichia coli into the genome of the mouse. One sequence was derived from the bacterial lac operon and the other was created by re-encoding the amino acid sequence of lacI with mammalian codons. Both versions are driven by an identical promoter fragment derived from the human beta-actin locus and were microinjected into genetically identical pronuclear stage embryos. All transgenes utilizing the bacterial coding sequence were transcriptionally silent in all somatic tissues tested. The sequence re-encoded with mammalian codons was transcriptionally active at all transgene loci and expressed ubiquitously. Using methylation-sensitive enzymes, we have determined the methylation status of lac repressor transgenes encoded by either the bacterial or mammalian sequence. The highly divergent bacterial sequence was hypermethylated at all transgene loci, while the mammalian sequence was only hypermethylated at a high copy number locus. This may reflect a normal process that protects the genome from acquiring new material that has an abnormally divergent sequence or structure.

Actins↗

PubMed2004

Genetic variation within and relationships among five subpopulations of Slovak Thoroughbred.

Genetic variation at six microsatellite loci was analysed for five Thoroughbred subpopulations to determine the magnitude of genetic differentiation and the genetic relationships among the subpopulations. Significant deviations from Hardy-Weinberg equilibrium were shown for a number of locus-population combinations, with all subpopulations. The genetic diversities and relationships of five Thoroughbred subpopulations were evaluated using six microsatellites recommended by the International Society of Animal Genetics (ISAG). The allele frequencies, the effective numbers of alleles, and the observed and expected heterozygosities were calculated. POPGENE v. 1.31 (Yeh et al., 1997) was used to test for deviations from the Hardy-Weinberg (H-W) equilibrium and to assign F(IS) estimates (Weir, 1990). The utility of microsatellites for evaluating genetic diversity of horses is discussed.

Animals↗

PubMed2000

Testing for concordant equilibria between population samples.

A substantial body of theory has been developed to assess the effect of evolutionary forces on the distribution of genotypes, both single and multilocus, within populations. One area where the potential for application of this theory has not been fully appreciated concerns the extent to which population samples differ. Within populations, the divergence of genotype or haplotype frequencies from that expected under Hardy-Weinberg (HW) or linkage equilibrium can be measured as disequilibria coefficients. To assess population samples for concordant equilibria, an analytical framework for comparing disequilibria coefficients between populations is necessary. Here we present log-linear models to evaluate such hypotheses. These models have broad utility ranging from conventional population genetics to genetic epidemiology. We demonstrate the use of these log-linear models (1) as a test for genetic association with disease and (2) as a test for different levels of linkage disequilibria between human populations.

Animals↗

PubMed2026

Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.

BACKGROUND: Polygenic risk scores (PRS) stratify inherited cardiovascular risk, but their path to clinical implementation remains unclear. OBJECTIVES: We aimed to develop and validate integrated PRS for 8 cardiovascular conditions and outline a framework for their clinical reporting. METHODS: We analyzed genotype and clinical data from 245,394 All of Us Research Program participants. Publicly available PRS for 8 traits-coronary artery disease, atrial fibrillation, type 2 diabetes, venous thromboembolism (VTE), thoracic aortic aneurysm (TAA), extreme hypertension, severe hypercholesterolemia, and elevated lipoprotein(a)-were combined using PRSmix, an elastic-net approach. Integrated PRS were externally validated in 53,306 Mass General Brigham Biobank participants using logistic regression, adjusting for age, sex, and ancestry. RESULTS: Of 53,306 genotyped Mass General Brigham Biobank participants (55.6% women, mean age 53 ± 17 years), integrated PRS demonstrated robust discrimination and appropriate calibration across 8 cardiovascular traits. Comparing high genetic risk (top 10% of PRS distribution, or top 20% for rarer TAA and VTE) vs average risk (26th-75th percentiles, or 21st-80th percentiles for TAA and VTE) yielded ORs: coronary artery disease (3.7 [95% CI: 3.4-4.1]), type 2 diabetes (3.1 [95% CI: 2.8-3.3]), atrial fibrillation (3.0 [95% CI: 2.7-3.3]), VTE (1.9 [95% CI: 1.6-2.0]), TAA (1.7 [95% CI: 1.5-1.9]), hypertension (2.1 [95% CI: 1.8-2.3]), hypercholesterolemia (4.1 [95% CI: 3.7-4.5]), and lipoprotein(a) (41.0 [95% CI: 27.0-62.2]). Incorporating integrated PRS into clinical models improved risk classification, while prospective analyses confirmed significant associations with incident cardiovascular outcomes. CONCLUSIONS: Integrated PRS offer an implementable framework for genetic risk reporting, and are now available as a clinically orderable test. Broader prospective validation studies are needed to further establish clinical utility.

Humans↗

PubMed1999

Preferences of women facing a prenatal diagnostic choice: long-term outcomes matter most.

Women aged 35 or older who wish to undergo prenatal diagnosis for chromosomal disorders are typically offered a choice between chorionic villus sampling or amniocentesis. These two tests are performed at different times and impose differing miscarriage risks. In deciding which test to use, therefore, women need to consider both short-term consequences (e.g. timing of pregnancy loss, should it occur) and long-term consequences (e.g. whether a pregnancy loss is followed by a future birth). We examined how women seeking prenatal diagnostic services value the outcomes of testing. We conducted a cross-sectional study of 72 women seeking genetic counselling at the University of California at San Francisco or Kaiser San Francisco. We measured preferences for outcomes (utilities) of prenatal diagnosis using the standard gamble metric. We also assessed demographics and attitudes via questionnaire. We observed no differences in mean utilities assigned to first- versus second-trimester pregnancy losses with similar long-term sequelae. Utilities for losses followed by future birth, however, were significantly higher than utilities for losses without future birth (range 0.91 to 0.93 versus 0.84 to 0.86, p<0.05 for all comparisons). In addition, we observed substantial variation in utilities across women. Long-term outcomes matter most to these women. In presenting prenatal diagnostic options to their patients, clinicians should include discussion of outcomes such as the likelihood of future birth in the event of a pregnancy loss. Furthermore, the substantial variation in utilities we observed suggests that future prenatal testing policies should account for the preferences of the individual woman.

Adult↗

PubMed2006

Rearrangements of chromosome 18 illustrate the utility of array-based comparative genomic hybridization.

Comprehensive and reliable testing is an important component of counseling and management in clinical genetics. Identification of imbalances of chromosomal segments has uncovered new genes and has established phenotype/genotype correlations for many syndromes with previously unidentified causes. Conventional cytogenetics has proven to be useful for the detection of large aberrations, but its resolution limits the identification of submicroscopic alterations. Comparative genomic hybridization (CGH) on a microarray-based platform has the potential to detect and characterize both microscopic and submicroscopic chromosomal abnormalities. Nine cases of aberrations involving chromosome 18 are used to illustrate the use and clinical potential of array CGH.

Child↗

PubMed1998

Genetic and economic responses for within-family marker-assisted selection in dairy cattle breeding schemes.

Marker-assisted selection schemes that utilize information about quantitative trait loci to preselect progeny test bulls within a family are the most practical application of quantitative trait loci results in the short-term. Technical difficulties exist for across-family marker-assisted selection using BLUP procedures. Two within-family marker-assisted selection schemes were evaluated genetically and economically using stochastic simulation for a locus that explained 5% of phenotypic variance. The genetic and economic impacts of variation in the number of offspring per bull-dam were evaluated. The top down marker-assisted selection scheme identifies sires that are heterozygous for the locus based on the granddaughter design and uses the quantitative trait locus information in the preselection of grandsons entering progeny testing. The bottom up marker-assisted selection scheme identifies sires heterozygous for a quantitative trait locus based on the daughter design and uses the information in the preselection of sons entering progeny testing. The top down scheme with one progeny per bull-dam reduced the rate of genetic gain compared with that from a breeding scheme that ignored knowledge of the quantitative trait locus. The top down scheme with reproductive performance of 3 or 40 progeny per bull-dam increased genetic gain by 1 to 2%. The bottom up scheme increased the rate of genetic gain by 1.5, 3.5, and 5% for 1, 3, and 40 progeny per bull-dam, respectively. When the top down scheme was used on the maternal path and the bottom up scheme on the paternal path, increases were 9% with 40 progeny per bull-dam. The use of reproductive technologies on bull-dams is imperative to prevent gains from marker-assisted selection being eroded by the loss in polygenic selection differential that results when more bull-dams are required to enable preselection of sons using markers.

Animals↗

PubMed1997

Who should provide genetic education prior to gene testing? Computers and other methods for improving patient understanding.

As numerous new gene tests are introduced into clinical practice, patients have a growing need for accurate and comprehensive information about the risks and benefits of gene testing. However, in the changing healthcare environment, it is not clear who will provide such information because genetic counselors are scarce and their services are not widely utilized, and primary care providers lack time and expertise in genetics. Interactive computers may help fill the information gap. We review a variety of educational modalities for providing patient education and argue that interactive computers have potential advantages over other educational methods for providing information and promoting informed consent to genetic testing. Finally, some questions for further research are raised.

Computer-Assisted Instruction↗

PubMed1992

Analysis of familial hypoalphalipoproteinemia syndromes.

Familial hypoalphalipoproteinemias (HA) are a heterogenous group of disorders characterized by various degrees of HDL deficiency. Differential diagnosis involves clinical and biochemical evaluation after intervention designed to correct known secondary causes of low HDL. Two specific HAs are discussed in this report: 1. primary isolated HA (PIHA) is a poorly characterized entity with an apparent autosomal dominant transmission and distinct abnormalities in the structure and function of HDL. 2. Lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes are caused by a number of different genetic defects that lead to at least two distinct clinical presentations i.e. familial LCAT deficiency and fish eye disease. PIHA is an example of a genetic disorder whose diagnosis would greatly be improved by the availability of molecular diagnostic tests. Conversely, the effect of the genetic heterogeneity of LCAT deficiency syndromes on diagnosis is best overcome by utilizing existing biochemical measurement of LCAT activity and the plasma cholesterol esterification rate.

Arteriosclerosis↗

PubMed2000

Intelligent control of a cryogenic cooling plant based on blackboard system architecture.

Intelligent system techniques have been rapidly assimilating into process control engineering, with many applications reported in the last decade. Intelligent control is bringing a new perspective as well as new challenges to process control. In this paper, a software architecture for a Blackboard for Integrated Intelligent Control Systems (BIICS) is described. The system is designed to simultaneously support multiple heterogeneous intelligent methodologies, such as neural networks. expert systems, fuzzy logic, neural networks and genetic algorithms. It will be shown how such methodologies can be readily assimilated into the software architecture. The BIICS system represents a multi-purpose platform for design and simulation of intelligent control paradigms for different kinds of processes. Currently the system utilizes intelligent control techniques (neuro-fuzzy and genetic optimization) for controlling a cryogenic plant used for superconductor testing at temperatures below 100 K.

Journal Article↗