SEARCH · PubMed Health

Results for “genetic test utilization”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources

PubMed1988

Enhancement of field stability and utility of future biologicals through prior accelerated degradation testing.

The scepticism about the future utility of newer biologicals towards reducing disease morbidity or mortality at the public health or application level can be regarded as appropriate. The financial or research inputs into producing anti-idiotypic, subunit, cloned or genetically engineered products may not be transcribed to the field level due to political or economic impediments and the putative breakdown of any specific activity at the application level, as with the conventional immunobiologicals, may also negate the utility of the newer products. Such an eventuality should be overcome by planning, during the pre-licensure phase, appropriate accelerated degradation tests on newer biologicals.

DNA, Recombinant↗

PubMed1992

Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two east Asian populations.

We examined the utility of the postdose 3-h plasma metabolic ratio (MR) as a phenotyping method for assessing genetically determined debrisoquine-type oxidation polymorphism after an oral dose of 100 mg of metoprolol tartrate administered to 402 unrelated, healthy, and native East Asian (218 Korean and 184 Japanese) subjects. All of them were phenotyped simultaneously with the reported MR employing urine samples collected during an 8-h postdose period. In the two populations, the distribution histograms and probit plots of log10plasma MRs derived from the metoprolol/alpha-hydroxymetoprolol concentration values indicated a large gap between the extensive and poor metabolizers who were phenotyped by the reported criteria of the 8-h urinary MR. There were statistically significant (p less than 0.001) correlations (rs = 0.688 and 0.810, respectively) between the postdose urinary and plasma MRs in the Korean and Japanese populations. Two poor metabolizers (one each included in the two racial groups) identified according to the 8-h urinary MR gave the greatest plasma MRs (i.e., 549.7 among the Koreans and 150.0 among the Japanese). The results suggest that the one-point, postdose 3-h plasma MR is also useful for the phenotyping purpose of oxidation pharmacogenetic polymorphism of metoprolol, a widely prescribed beta-adrenoceptor blocking drug.

Adolescent↗

PubMed2006

The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. METHODS: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. RESULTS: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). DISCUSSION: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.

Cooperative Behavior↗

PubMed1996

Future approaches to genetic toxicology risk assessment.

Short-term genetic toxicology tests were developed for the purpose of identifying chemical carcinogens in the environment. After two decades of development and validation, the tests are well-established in routine testing schemes, but our views of their utility for safety evaluation have undergone re-assessment. The correlation between identified mutagens and identified carcinogens has turned out to be significantly less than one. Processes or mechanisms that are not directly genotoxic appear to play a role in carcinogenesis. While short term test data are still components of the assessment of carcinogenic risk, genetic damage also has been recognized as important in its own right, in relation to heritable genetic risk and other health-related effects, such as aging, reproductive failure and developmental toxicity. The revolution in molecular biology and genetic analysis occurring over the past 20 years has contributed to the wealth of new information on the complexities of cell regulation, differentiation, and the carcinogenic process. These technologies have provided new experimental approaches to genetic toxicology assessments, including transgenic cell and animal models, human monitoring, and analysis of macromolecular interactions at environmentally relevant exposures. The potential exists for the development of more efficient and more relevant genetic toxicology testing schemes for use assessing human safety. A delineation of contemporary needs, a modern view of the elements of cancer induction, and an examination of new assays and technologies may provide a framework for integrating new approaches into current schemes for evaluating the potential genetic and carcinogenic risk of environmental chemicals.

Animals↗

PubMed2003

Gradual evolution in bacteria: evidence from Bacillus systematics.

The bacterial genome projects have suggested a central role for horizontal transfer in bacterial adaptation, but it is difficult to rule out an adaptive role for ordinary genetic change in existing genes. The bacterial systematics literature can readily address the importance of gene acquisition in adaptive evolution, since phenotypic characterization typically assesses presence versus absence of metabolic capabilities, and metabolic gains and losses are most likely due to horizontal transfer and/or gene loss. Bacterial systematists have not geared their studies toward quantitative differences in metabolic capabilities, which are more likely to involve adjustments of existing genes. Here, quantitative variation in metabolism within and between three closely related Bacillus taxa has been assayed. While these taxa show no qualitative (i.e. presence versus absence) differences in resource utilization, they are quantitatively different in utilization of 8 % of 95 resources tested. Moreover, 93 % of the resources tested showed significant quantitative variation among strains within a single taxon. These results suggest that ordinary genetic changes in existing genes may play an important role in adaptation. If these results are typical, future genomically based assays of quantitative variation in phenotype (e.g. microarray analysis of mRNA concentrations) may identify hundreds of genes whose expression has been modified. A protocol is presented for identifying those modifications of gene expression and those gene acquisitions that are most likely to have played a role in adaptive evolution.

Adaptation, Physiological↗

PubMed1997

Estimates of genetic parameters for a test day model with random regressions for yield traits of first lactation Holsteins.

A model that contains both fixed and random linear regressions is described for analyzing test day records of dairy cows. Estimation of the variances and covariances for this model was achieved by Bayesian methods utilizing the Gibbs sampler to generate samples from the marginal posterior distributions. A single-trait model was applied to yields of milk, fat, and protein of first lactation Holsteins. Heritabilities of 305-d lactation yields were 0.32, 0.28, and 0.28 for milk, fat, and protein, respectively. Heritabilities of daily yields were greater than for 305-d yields and varied from 0.40 to 0.59 for milk yield, 0.34 to 0.68 for fat yield, and 0.33 to 0.69 for protein yield. The highest heritabilities were within the first 10 d of lactation for all traits. Genetic correlations between daily yields were higher as the interval between tests decreased, and correlations of daily yields with 305-d yields were greatest during midlactation.

Algorithms↗

PubMed2006

Allele frequency distribution based on 17 STR markers in three major Dravidian linguistic populations of Andhra Pradesh, India.

Allele frequencies for 15 tetranucleotides and 2 pentanucleotides repeat loci were determined in 317 unrelated, healthy individuals of Andhra Pradesh, India, belonging to three pre-dominant endogamous populations namely, Kappu Naidu, Kamma Chaudhary and Kapu Reddy. Adherence to the expectations of the Hardy-Weinberg equilibrium (HWE) was confirmed for all loci with few exceptions, which were not significant after applying Bonferroni's correction. Statistical parameters of forensic interest; observed heterozygosity, probability of homozygosity, probability of extact test, power of discrimination, match probability, polymorphism information content, power of exclusion and mean paternity index were determined for all loci. The present study reveals that Penta E and D2S1338 are the most informative loci in all the studied populations. The combined power of discrimination was greater than 0.976, whereas the cumulative power of exclusion gave an expected value of 0.9999 for all the tested microsatellite loci. No difference was observed in the discriminatory power of 15 loci in studied populations on comparison with other populations of India. Population differentiation tests revealed significant differences between the studied and neighboring populations at several loci. Analyzed parameters indicate the utility and efficacy of the studied 17 STR systems as a powerful tool in forensic human identification, paternity testing and human population genetic studies.

DNA Fingerprinting↗

PubMed2002

Modelling haematopoietic malignancies in the mouse and therapeutical implications.

Modelling human disease in the mouse has become an essential activity in biomedical research in order to unravel molecular mechanisms underlying pathological conditions as well as to determine in vivo the consequences of aberrant gene function. The mouse is by far the most accessible mammalian system physiologically similar to humans. Furthermore, the development of novel techniques for manipulating the murine genome, which allow the in vivo modification of virtually any genomic region in a time and/or tissue specific manner, renders the mouse an ideal model system to study human pathological conditions. Modelling human diseases in mice has reached an even greater relevance in the field of haematological malignancies, due to the already advanced characterization of the molecular basis of many haematological disorders. In this review, we describe the most important technological developments that made it possible to reproduce in the mouse the genetic lesions that characterize human haematological malignancies, thus often generating faithful mouse models of the human condition. We provide specific examples of the advantages and limitations of the various genetic approaches utilized to model leukaemia and lymphoma in the mouse. Finally, we discuss the power of mouse modelling in developing and testing novel therapeutic modalities in pre-clinical studies.

Animals↗

PubMed1998

Genetics and biology of gynecologic cancer.

Gynecologic epithelial tumors can be grouped into two major categories depending on whether they are derived embryologically from squamous epithelium of the urogenital sinus or from müllerian ducts. Ovarian carcinomas appear morphologically similar to those arising in müllerian-derived organs, and molecular genetic defects present in tumors from these different sources appear to reflect more their histologic subtypes than their organ of origin. The possibility that ovarian epithelial tumors arise from remnants of müllerian ducts in the vicinity of the ovary therefore merits further investigation. Recent advances in our understanding of the state of clonality of various gynecologic tumors, of the influence of age and ovulatory activity on their genetic characteristics, and of their overall molecular genetic features, provide important clues about their initial underlying mechanisms. Novel strategies based on these advances are being tested for their potential utility in treating and monitoring gynecologic tumors.

Endometrial Neoplasms↗

PubMed1996

Regulatory Genes Controlling MPG1 Expression and Pathogenicity in the Rice Blast Fungus Magnaporthe grisea.

MPG1, a pathogenicity gene of the rice blast fungus Magnaporthe grisea, is expressed during pathogenesis and in axenic culture during nitrogen or glucose limitation. We initiated a search for regulatory mutations that would impair nitrogen metabolism, MPG1 gene expression, and pathogenicity. First, we developed a pair of laboratory strains that were highly fertile and pathogenic toward barley. Using a combinatorial genetic screen, we identified mutants that failed to utilize a wide range of nitrogen sources (e.g., nitrate or amino acids) and then tested the effect of these mutations on pathogenicity. We identified five mutants and designated them Nr- (for nitrogen regulation defective). We show that two of these mutations define two genes, designated NPR1 and NPR2 (for nitrogen pathogenicity regulation), that are essential for pathogenicity and the utilization of many nitrogen sources. These genes are nonallelic to the major nitrogen regulatory gene in M. grisea and are required for expression of the pathogenicity gene MPG1. We propose that NPR1 and NPR2 are major regulators of pathogenicity in M. grisea and may be novel regulators of nitrogen metabolism in fungi.

Journal Article↗

PubMedDate not supplied

Molecular signals regulating proliferation of stem and progenitor cells in mouse olfactory epithelium.

To understand how signaling molecules regulate the generation of neurons from proliferating stem cells and neuronal progenitors in the developing and regenerating nervous system, we have studied neurogenesis in a model neurogenic epithelium, the olfactory epithelium (OE) of the mouse. Our studies have employed a candidate approach to test signaling molecules of potential importance in regulating neurogenesis and have utilized methods that include tissue culture, in situ hybridization and mouse genetics. Using these approaches, we have identified three distinct stages of stem and transit amplifying progenitor cells in the differentiation pathway of olfactory receptor neurons (ORNs) and have identified mechanisms by which the development of each of these progenitor cell types is regulated by signals produced both within the OE itself and by its underlying stroma. Our results indicate that regulation of olfactory neurogenesis is critically dependent on multiple signaling molecules from two different polypeptide growth factor superfamilies, the fibroblast growth factors and the transforming growth factor beta (TGF-beta) group. In addition, they indicate that these signaling molecules interact in at least two important ways: first, opposing signals converge on cells at specific developmental stages in the ORN pathway to regulate proliferation and differentiation; and second, these signaling molecules--particularly the TGF-betas and their antagonists--play key roles in feedback loops that regulate the size of progenitor cell pools and thereby neuron number, during development and regeneration.

Animals↗

PubMed2006

Reduced human and murine corneal thickness in an Axenfeld-Rieger syndrome subtype.

PURPOSE: Axenfeld-Rieger malformations of the anterior segment are clinically heterogeneous, and up to 50% of cases are attributable to PITX2 or FOXC1 mutation. In view of PITX2's contribution to corneal development and the altered CCT in some FOXC1-related cases, this study was undertaken to investigate whether a related phenotype is associated with the PITX2/Pitx2 mutation. METHODS: Central corneal thickness (CCT) was measured in patients and mice with PITX2/Pitx2 mutations. CCT in affected individuals and unaffected first-degree relatives from a large PITX2 mutation pedigree was measured with ultrasonic pachymetry. For murine measurements, the optical coherence tomogram (OCT) was calibrated against plastic films whose thickness had been determined with scanning electron microscopy (SEM). Subsequently, CCT was measured in ex vivo eyes from Pitx2(+/-) and wild-type murine littermates by using OCT. RESULTS: CCT in individuals with the PITX2 mutation (mean 484 microm; range, 425-519; n = 8) was significantly lower than in their unaffected first-degree relatives (mean 582 microm; range, 550-590; n = 5; P = 0.0002, t-test). Scanning electron microscopy (SEM) and OCT measurements of reference films correlated closely (r = 0.9995) and subsequent OCT analysis of murine eyes revealed a significant reduction in CCT in Pitx2(+/-) compared with wild-type littermates (Pitx2(+/-): mean, 72 microm; range, 57-87, n = 6; wt: mean, 88 microm; range, 63-100; n = 6, P = 0.035, t-test). CONCLUSIONS: The results show that PITX2/Pitx2 mutation results in reduced corneal thickness and provides the first example of reduced CCT in a genetic subtype of glaucoma. These data will facilitate management of developmental glaucoma and offer potential for guiding molecular genetic testing in patients with Axenfeld-Rieger. The similar CCT reduction observed in patients and mice with comparable mutations emphasizes the utility of this murine model. The technical advance of optical murine CCT measurement also provides scope for serial in vivo imaging of the developing anterior segment and determining the effects of altered CCT on measured IOP.

Animals↗

PubMed2004

Association between the interleukin-1beta C(-511)T polymorphism and blood pressure in a Chinese hypertensive population.

The interleukin-1beta (IL-1beta) is an important pro-inflammatory cytokine in a broad spectrum of physiological processes. Previous investigations have observed that levels of the IL-1beta were higher in essential hypertensive patients and the IL-1beta gene polymorphism has been shown to be related to IL-1 production. We hypothesized that genetically determined differences in activity or responsiveness of cytokine(s) might contribute to hypertension. In this report, we utilized a family-based design to test the association between the IL-1beta C(-511)T polymorphism and blood pressure levels in hypertensive patients chosen from rural communities in Anhui, China. In men, carriers of the IL-1beta (-511)*C allele were found to have lower systolic (P = 0.049) blood pressure levels compared with T homozygotes, which conforms to an additive effect model. By contrast, no significant association between the IL-1beta gene and blood pressure levels was revealed in women. Our results suggested a significant role of the IL-1beta C(-511)T polymorphism in the control of blood pressure in Chinese hypertensives.

Asian People↗

PubMed2026

Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.

BACKGROUND AND AIMS: Comprehensive genomic profiling (CGP) for tumors and germline genetic testing (GGT) inform precision therapy and clinical management of patients with colorectal cancer (CRC), and evidence is growing in support of universal paired CGP-GGT patient testing. However, the utility of combining CGP and GGT for early-stage CRC (ESC) and early-onset CRC (EOC) is unclear. METHODS: We performed a prospective, multisite study featuring GGT using an 80+ gene next-generation sequencing platform and exome-based CGP among CRC patients (unselected for age, stage, family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: A total of 150 CRC patients had GGT and exome-based CGP performed. ESC patients had an enrichment of high microsatellite instability and high tumor mutation burden. High microsatellite instability was also enriched in those with smoking history, and in tumors with mutated BRAF, homologous recombination deficiency, or at least 1 variant in the rat sarcoma virus pathway. Moreover, patients with smoking history were enriched in BRAF and other Tier 1 or 2 variants overall. Sixteen percent of patients harbored a pathogenic germline variant, most frequent being in Lynch syndrome genes. Paired GGT and CGP testing had high rates of clinically significant findings (≈70%) with the most frequent being high tumor mutation burden status. Pathway and mutational signature analysis revealed frequent CGP mutations in DNA repair and cell cycle pathways. CONCLUSION: These data suggest that universal, combined GGT-CGP increases clinical utility for EOC and ESC patients. This is key for EOC patients who tend to experience poorer outcomes. CGP-GGT expedites germline resolution for tumor mutations in hereditary cancer genes, reducing delays and facilitating identification of relevant therapies, clinical trials, and management recommendations.

Colorectal Cancer↗

PubMed2001

The activation of a neocentromere in Drosophila requires proximity to an endogenous centromere.

The centromere is essential for proper segregation and inheritance of genetic information. Centromeres are generally regulated to occur exactly once per chromosome; failure to do so leads to chromosome loss or damage and loss of linked genetic material. The mechanism for faithful regulation of centromere activity and number is unknown. The presence of ectopic centromeres (neocentromeres) has allowed us to probe the requirements and characteristics of centromere activation, maintenance, and structure. We utilized chromosome derivatives that placed a 290-kilobase "test segment" in three different contexts within the Drosophila melanogaster genome--immediately adjacent to (1) centromeric chromatin, (2) centric heterochromatin, or (3) euchromatin. Using irradiation mutagenesis, we freed this test segment from the source chromosome and genetically assayed whether the liberated "test fragment" exhibited centromere activity. We observed that this test fragment behaved differently with respect to centromere activity when liberated from different chromosomal contexts, despite an apparent sequence identity. Test segments juxtaposed to an active centromere produced fragments with neocentromere activity, whereas test segments far from centromeres did not. Once established, neocentromere activity was stable. The imposition of neocentromere activity on juxtaposed DNA supports the hypothesis that centromere activity and identity is capable of spreading and is regulated epigenetically.

Animals↗

PubMed1996

Managed genetic care in a large HMO.

Comprehensive clinical genetic services are offered to 2.4 million members by the Kaiser Permanente Medical Care Program (KP), a not-for-profit HMO, in its Northern California region. Four genetics centers are staffed by clinical geneticists, genetic counselors, nurses, and laboratory technologists, who together provide patient and physician education, genetic screening, and prenatal, infant, and adult evaluation. Besides offering lectures and teleconferences, the geneticists publish a newsletter on how to use the genetic services for approximately 1200 pediatricians, obstetricians, and other relevant specialists. Clinical services offered to members include individual, group, and telephone consultations, and easy access to geneticists is provided for primary care providers with genetic care questions. In-house laboratory services include blood and tissue cytogenetic analysis, DNA testing, and prenatal blood and amniotic fluid testing. A large database and a comprehensive and cost-effective program of genetic services have been developed. An interregional genetics data system is being established to link Northern and Southern California and the Northwest (Portland and Hawaii regions). Steps are also underway to include other regions in the database and to encourage utilization of regionalized KP genetic laboratories by smaller regions.

California↗

PubMed1978

Introduction: utilization of higher plant systems as monitors of environmental mutagens.

Research over the past 10 years has clearly demonstrated the presence of mutagens among the numerous man-made and naturally occurring chemicals in our environment. These mutagens occur in all classes of chemicals, including foods, drugs, cosmetics, pesticides, household and industrial chemicals as well as in pollutants of both air and water. More recently, a high correlation has been found between carcinogenic and mutagenic activity; at least 90-95% of chemical carcinogens are mutagens. There is a widespread expectation that the discovery of mutagenic activity in chemical screening programs may alert us not only to mutagenic potential in man, but carcinogenic potential as well. The types of genetic damage which can be produced are numerous and the specificity of chemical mutagens makes it possible for one type of effect to be produced predominantly or exclusively. Thus, any screening program must consist of a battery of tests capable of detecting nondisjunction, chromosome aberrations, gene mutations (point mutations as well as interstitial deletion), in addition to more subtle effects of DNA repair. In addition, since innocuous chemicals can be converted by mammalian metabolism to potent mutagens and carcinogens, these metabolites must be evaluated as well as the parent compounds. Chemicals such as air pollutants present particular problems for mutagenicity testing using conventional microbial assays. Some of these problems can be overcome by using various higher plant systems. The general utility of these systems needs to be evaluated in terms of the types of genetic damage which can be detected, relative sensitivity, and general utility for use in mutagen screening and monitoring.

Biological Assay↗

PubMed1990

The genetics of insulin-dependent diabetes in the BB rat.

Very little is known about the genes involved in the pathogenesis of IDDM. One component is known to be linked to the major histocompatibility complex, but the other components are unknown. We know from the major animals models of IDDM, both the NOD mouse and the BB rat, that the disease is under multigenic control. However, due to the size and complexity of the mammalian genome as well as to the lack of useful clues, the location and identity of the other genes remains a mystery. This is compounded by the fact that well-characterized genetic markers are not available for all regions of the mammalian genome, and it is likely that at least some of the genes of interest are located in these regions. The testing of pedigrees for the linkage of RFLP with the genetic factors involved in IDDM promises to be the most effective means of mapping, and ultimately identifying, these genes. However, the number of genes which are theoretically necessary to test for linkage makes even this approach impractical. Here, we have described here how the amount of work and time can be significantly reduced by utilizing repetitive DNA sequences as probes for the linkage of random RFLPs to diabetes. With each screening, one can simultaneously test multiple unlinked loci in the genome. Preliminary results which show promising linkage to two of the genetic components have been presented, thereby supporting the usefulness of this approach.

Animals↗