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PubMed2000

Adverse selection and categorical discrimination in the health insurance markets: the effects of genetic tests.

In this paper, the effects of new methods for risk classification, e.g., genetic tests, on health insurance markets are studied using an insurance model with state contingent utility functions. The analysis focuses on the case of treatment costs higher than the patient's willingness to pay where standard models of asymmetric information are not applicable. In this case, the benefit from signing a fair insurance contract will be positive only if illness probability is low. In contrast to the common perception, additional risk classification under symmetric information can be efficiency enhancing. Under asymmetric information about illness risks, however, there can be complete market failure.

Genetic Testing↗
PubMed1987

Plant genetic resources: prediction by isozyme markers and ecology.

Linkage or association of genetic markers to quantitative traits of agronomic importance can substantially simplify the genetic analysis of complex quantitative traits. Enzyme marker genes are ideal candidates for quantitative genetic analysis. We have recently applied this powerful methodology to the analysis of genetic resources of wild cereals in Israel, primarily wild emmer wheat, Triticum dicoccoides, and wild barley, Hordeum spontaneum, the progenitors of cultivated wheats and barley, respectively. We have found that allelic isozyme markers and ecological factors provide an important predictive method for identifying elite genotypes characterized by single or multiple disease resistances, high protein content, and a variety of quantitative traits of agronomic importance including germination, earliness, biomass, and yield variables. Our predictive methodology could be improved by additional crossing tests in an attempt to verify the results derived from the correlation analysis and thus establish the linkage relationships between the marker gene and the quantitative trait under discussion. This methodology, if further developed by additional isozyme and DNA markers, verified by crossing tests and gene mapping, could substantially contribute to the sampling and utilization of the genetic resources of wild gene pools for crop improvement.

Agriculture↗
PubMed1992

A conserved region in human and Chinese hamster X chromosomes can induce cellular senescence of nickel-transformed Chinese hamster cell lines.

Cellular senescence is the genetically programmed cessation of cellular proliferation. We have recently mapped a putative senescence gene(s) on the X chromosome of Chinese hamster embryo (CHE) cells. In the present study, we have utilized microcell-mediated chromosome transfer (microcell fusion) to test whether: (i) the human X chromosome exhibits similar genetic potential to induce senescence and (ii) the deletion or inactivation of the X-linked senescence gene(s) in CHE cells is associated with nickel-induced immortalization. A normal CHE or human X chromosome was first introduced into mouse-cell hybrids, then transferred by microcell fusion into a nickel-transformed, immortal male CHE cell line (Ni-2/TGR) with an X deletion (Xq1). Microcell fusion of the normal CHE X chromosome into tumorigenic Ni-2/TGR cells yielded senescence of all X recipient clones. The normal human X chromosome induced dominant senescence of tumorigenic Ni-2/TGR cells in only 17% of the resulting microcell hybrids (14/81). Karyotypic analyses of 13 non-senescing human X chromosome-derived microcell hybrid clones revealed that none of these clones retained the complete X. A normal CHE X chromosome induced senescence of 75% of hybrids obtained with another immortal and tumorigenic nickel-transformed male CHE cell line (Ni-6/TGR), which exhibited no visible deletion of the X chromosome, while the normal human X chromosome, only induced senescence in 19% of these hybrids. Transfer of the normal CHE or human X chromosome into spontaneously transformed and tumorigenic cell lines, CHO/TGR or V79/TGR, had little or no effect on their growth. These data suggest that both human and CHE cells possess similar X-linked genetic activities that regulate the process of cellular senescence, and that in Chinese hamster cells nickel-induced immortalization but not that of CHO or V79 cells is associated with inactivation of an X-linked senescence gene.

Animals↗
PubMed1977

The use of yeast cultures for the detection of environmental mutagens using a fluctuation test.

A microbial fluctuation test, modified for the detection of environmental mutagens has been evaluated using a number of strains of the yeast Saccharomyces cerevisiae. Auxotrophic diploid cultures of yeast which produce prototrophic colonies by both mitotic gene conversion and mutation have been extensively utilized for the detection and evaluation of chemicals showing genetic activity. A number of the yeast strains utilized were shown to be suitable for use in the fluctuation test although the time scales of the experiments were considerably extended (up to 16 days) compared to those involving bacteria. The yeast strains respond to doses of mutagens at least a 100-fold lower than that required in a conventional short exposure treat and plate experiment. In experiments involving the induction of mitotic gene conversion at the tryptophan-5 and histidine-4 loci in the fluctuation test significant increases in prototrophic cells were produced in the presence of the insecticide Lindex (0.05 microng/ml), the preservative Thiomersal (0.0001 microng/ml), a mahogany hair dye (0.01 microng/ml), the herbicide Paraquat (0.02 microng/ml) and the alkylating agent ethyl methane sulphonate (0.1 microng/ml). The results demonstrate that the fluctuation test provides an extremely sensitive assay for the detection of chemicals which show genetic activity in yeast at non-toxic concentrations.

Biological Assay↗
PubMed2003

Tumor markers and colorectal cancer: utility in management.

Colorectal cancer (CRC) is a leading cause of morbidity and mortality. Although genetic testing can screen for rare hereditary CRC syndromes, there is no ideal means of screening for sporadic forms of CRC. This review will focus on markers that are currently used in the management of sporadic CRC and their limitations, as well as possible future clinical applications.

Adenomatous Polyposis Coli↗
PubMed2002

Inference of a genetic network by a combined approach of cluster analysis and graphical Gaussian modeling.

MOTIVATION: Recent advances in DNA microarray technologies have made it possible to measure the expression levels of thousands of genes simultaneously under different conditions. The data obtained by microarray analyses are called expression profile data. One type of important information underlying the expression profile data is the 'genetic network,' that is, the regulatory network among genes. Graphical Gaussian Modeling (GGM) is a widely utilized method to infer or test relationships among a plural of variables. RESULTS: In this study, we developed a method combining the cluster analysis with GGM for the inference of the genetic network from the expression profile data. The expression profile data of 2467 Saccharomyces cerevisiae genes measured under 79 different conditions (Eisen et al., PROC: Natl Acad. Sci. USA, 95, 14683-14868, 1998) were used for this study. At first, the 2467 genes were classified into 34 clusters by a cluster analysis, as a preprocessing for GGM. Then, the expression levels of the genes in each cluster were averaged for each condition. The averaged expression profile data of 34 clusters were subjected to GGM, and a partial correlation coefficient matrix was obtained as a model of the genetic network of S. cerevisiae. The accuracy of the inferred network was examined by the agreement of our results with the cumulative results of experimental studies.

Bayes Theorem↗
PubMed2002

A heteroduplex method for detection of targeted sub-populations of bacterial communities.

We describe a simple method, based on heteroduplex mobility analysis of 16S rDNA fragments, for targeted detection of sub-populations of bacteria within diverse microbial communities. A small (ca. 200 bp) polymorphic fragment of the bacterial 16S rRNA gene was amplified from sample DNA using universal primers. Sample products were hybridised with a fluorescently labelled fragment amplified from a selected 'reporter' organism representing the target group. The resulting products were resolved and the labelled heteroduplex pairs detected on non-denaturing gels using automated DNA detection technology. A model, based on analysis of samples with known 16S rDNA sequences, demonstrates that heteroduplex mobility is inversely correlated with genetic distance and that beyond 26% genetic difference, heteroduplex products are not detected. The utility of the method was tested by field studies in which stream biofilms could be characterised by heteroduplex profiles generated with heterotrophic and autotrophic reporter organisms representing target groups.

Bacteria↗
PubMed2006

[Pharmacogenetic testing: utility in drug development and in routine clinical practice].

Pharmacogenetic tests can identify the role of genetic factors in the inter-individual variability of drug responsiveness. This variability can involve three systems, namely drug-metabolizing enzymes, transmembrane drug transporters, and drug effctor sites (receptors, enzymes, ion, channels, etc.). At present, pharmacogenetic testing is rarely used in clinical practice. A rapid survey of the four laboratories conducting such tests for Paris hospitals shows that about 750 tests were done during a 12-months period in 2004-2005, and that most focused on allelic variants of drug-metabolizing enzymes. Three other European laboratories perform between 25, and 7.000 tests per year. However, the number of pharmacogenetic tests is set to grow rapidely in the near future. The role of genetic factors in adverse drug reactions (ADR) has not yet been the subject of a systematic study. Drug-drug interactions that inhibit or induce certain enzyme activities are a major cause of adverse reactions, but they have not been exhaustively studied Pharmacogenetic and pharmacogenomic tools are increasingly used in the drug development process. This should result in the discovery of new therapeutic targets and in a better understanding of factors governing drug efficacy and tolerability. DNA samples are already collected systematically in many phase II and III clinical trials, and registration agencies such as the FDA are establishing guidelines for the submission of pharmacogenetic data on new drugs. These efforts, together with DNA samples collection during post-registration pharmacoepidemiological studies, should help to understand inter-individual variability in drug efficacy and tolerability. They may also result in the identification of new drug targets and will help to tailor therapy to the individual patient.

Clinical Medicine↗
PubMedDate not supplied

Some genetic considerations for the design of better mammalian assay systems for the detection of chemical mutagens and carcinogens.

Fuller utilization of the potential for genetic manipulation of the laboratory animal populations producing test animals should aid in the development of more sensitive, relevant, and economic toxicologic assay systems for the generation of dose response data at environmental exposure levels. One example of such genetic manipulation is the incorporation, in laboratory mouse populations of any desired genetic structure, of dominant visible mutations which enhance tumor formation. Thus, two different levels of inherent susceptibility to tumor formation can be incorporated and visually identified in the same test population. Another example is the manipulation of the genetic structure of a laboratory animal population in order to generate F-1 hybrids, hybrid crosses, or minimally inbred stocks from the same gene pool. Which of these genetic structures is most suitable in any particular case depends on the purpose for which the assay data are to be used. In making a choice, the desired degree of genetic heterogeneity of the population and the phenotypic variability of the toxicologic responses to be assayed must be considered.

Animals↗
PubMed1997

Genetic susceptibility to breast and ovarian cancer.

5-10% of women with breast cancer carry an inherited mutation in either the BRCA1 or BRCA2 genes. These genes confer a very high lifetime risk of breast cancer, ovarian cancer (especially BRCA1) and male breast cancer (especially BRCA2). These genes are large, of essentially unknown function, and surprisingly, play a very small role in the development of tumors in non-predisposed individuals. These genes have now been cloned, a highly automated genetic test developed and high risk populations have been screened to establish the utility of the test. The value to women and preliminary clinically recommendations are discussed.

BRCA1 Protein↗
PubMed2000

Risk estimation and value-of-information analysis for three proposed genetic screening programs for chronic beryllium disease prevention.

Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP beta 1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (approximately 94%) but low specificity (approximately 70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD evaluations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

Berylliosis↗
PubMed2005

[Serological and genetic markers in the diagnosis and follow-up of coeliac disease].

INTRODUCTION: Understanding of celiac disease has changed with the advent of serological markers (antigliadin IgA, anti-endomysial IgA and anti-transglutaminase IgA antibodies) and with the identification of major susceptibility genes (HLA-DQA1*05-DQB1*02). Reports of the efficacy of these diagnostic tests have varied, depending on the methodology used and the population investigated. OBJECTIVES: To determine the clinical utility of genetic and serological markers in the diagnosis of celiac disease, their relationship with histological lesions and their changes during treatment, in order to establish an optimal diagnostic algorithm in our environment. PATIENTS AND METHODS: We performed a retrospective study of 590 patients from the health area of Badajoz referred to the Immunology Laboratory for screening or follow-up of celiac disease. The results of intestinal histology, serological markers (antigliadin IgA, anti-endomysial IgA and anti-transglutaminase IgA antibodies), and genomic typing (HLA-DQA1*05-DQB1*02) were analyzed. RESULTS: The sensitivity and specificity of serological tests were greater than 90 %, with a negative predictive value of 98-100 %. HLA-DQA1*05-DQB1*02 was detected in 97 % of celiac patients, with a very high negative predictive value (99 %). On biopsy, 95 % of the patients with some grade of intestinal lesion were positive for antigliadin and/or anti-endomysial antibodies. CONCLUSION: To avoid missed diagnoses, the diagnostic algorithm of celiac disease should include at least two serological markers (antigliadin antibodies and anti-endomysial and/or anti-transglutaminase antibodies) and IgA quantification. Genomic typing should be carried out if one or more markers are positive or if the subject belongs to any of the risk groups. The physician should decide on the advisability of intestinal biopsy on the basis of the patient's clinical and immunological history.

Atrophy↗
PubMed2005

Reproductive decision making before and after predictive testing for Huntington's disease: an Australian perspective.

A retrospective study examined both pre- and post-result reproductive decision making for 281 people at risk for Huntington's disease aged 18-45 years who had undergone predictive testing in one centre in Australia between 1990 and 2002. Forty-eight per cent of subjects had one or more pre-result pregnancies, and of these, three had prenatal linkage testing. One high-risk (50%) pregnancy was terminated. Four couples chose an alternative reproductive option. Following testing, data were available for 231 subjects, and no significant difference was found between mutation carriers and non-carriers in the occurrence of post-result pregnancies. This contrasts with the finding of a recent European study, although the outcome of the present study may have been influenced by loss of follow-up data for 50 subjects. Five carriers (17%) had a total of six prenatal tests. Four showed a carrier result and these pregnancies were terminated. Two carriers utilized an alternative reproductive option (donor insemination and pre-implantation genetic diagnosis). The results of this study confirm previous findings of a low uptake of prenatal testing and alternative reproductive options by people at risk for Huntington's disease undergoing predictive testing.

Abortion, Induced↗
PubMed2000

Mouse genetics/genomics: an effective approach for drug target discovery and validation.

The mouse has become the premier mammalian system for the identification of the genetic basis of both mono- and oligogenic disorders, as well as the understanding of complex diseases with gene-gene and gene-environment interactions. The similarity between human and mouse genetic disease is sometimes striking, while in other cases the phenotypes are less similar. The ability to genetically map and then clone single gene disorders rapidly, and the emerging technologies that will allow the economical identification of the polygenes controlling quantitative traits further demonstrate the utility of the mouse as a model for gene discovery. Additionally, the ability to genetically manipulate the mouse through transgenesis and gene targeting allows for the testing of hypotheses regarding specific gene function and their role in disease. The utility of the mouse extends beyond being just a gene discovery tool to provide prevalidated targets. It can also be used for the development of animal models, and the testing of compounds in specifically constructed transgenic and knockout strains to further define the target and pathway of a therapeutic compound.

Amino Acid Sequence↗
PubMed2006

The admixture linkage disequilibrium and genetic linkage inference on the gradual admixture population.

Through the theoretical analysis of the admixture linkage disequilibrium (ALD) in the gradual admixture (GA) model, in which admixture occurs in every generation, the ALD is found to be proportional to the difference in marker allele frequencies, P1 - P2, between two subpopulations. Based on this property, we can employ a strict monotonic function (delta(ker) = delta/(P1-P2), where delta denotes the linkage disequilibrium (LD)) of the recombination fraction between the marker locus and the disease locus to infer the true genetic linkage. We construct a quasi likelihood ratio test (LRT) for the case-only data utilizing the information of unlinked markers in the human genome. The simulation results show that our tests can be used to fine map a disease locus. The effects of parameter values in the ALD mapping are also discussed.

Black or African American↗
PubMed2006

Mapping cis-acting regulatory variation in recombinant congenic strains.

We present an integrated approach for the enriched detection of genes subject to cis-acting variation in the mouse genome. Gene expression profiling was performed with lung tissue from a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J inbred mouse strains. A multiple-regression model measuring the association between gene expression level, donor strain of origin (DSO), and predominant strain background identified over 1,500 genes (P < 0.05) whose expression profiles differed according to the DSO. This model also identified over 1,200 genes whose expression showed dependence on background (P < 0.05), indicating the influence of background genetic context on transcription levels. Sequences obtained from 1-kb segments of 3'-untranslated regions identified single nucleotide polymorphisms in 64% of genes whose expression levels correlated with DSO status, compared with 29% of genes that displayed no association (P < 0.01, Fisher exact test). Allelic imbalance was identified in 50% of genes positive for expression-DSO association, compared with 22% of negative genes (P < 0.05, Fisher exact test). Together, these results demonstrate the utility of RCS mice for identifying the roles of proximal genetic determinants and background genetic context in determining gene expression levels. We propose the use of this integrated experimental approach in multiple tissues from this and other RCS panels as a means for genome-wide cataloging of genetic regulatory mechanisms in laboratory strains of mice.

Allelic Imbalance↗
PubMed2024

Payer perspectives on genomic testing in the United States: A systematic literature review.

PURPOSE: Health care stakeholders' perspectives on the value of genomic testing vary widely and directly affect the access and practice of genomic medicine. To our knowledge, a review of US health care payers' perspectives on genomic testing has not been performed. METHODS: We conducted a systematic literature review of US payers' perspectives on genomic testing in the MEDLINE, PubMed, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Of the 161 nonduplicate records screened, we summarized findings from 20 included records, and using the framework method, common domains were recorded. RESULTS: Domains included clinical utility, coverage decision frameworks, potential harms, costs, paying for research, demand/pressure, the flexibility of outcomes considered, and personal utility. There was consensus on the definition of clinical utility as improved health outcomes, and the nuances of genomic testing were reported as challenging to fit within existing coverage decision frameworks. Perspectives varied on accepting broader outcomes or uses of genomic testing and whether costs influence coverage decisions. Study methodologies were heterogeneous. CONCLUSION: A deeper understanding of how payers approach genomic testing may allow comparison with other stakeholders' perspectives and may identify challenges, opportunities, and solutions to align a conceptual and evidentiary framework better to demonstrate the value of genomic testing.

Humans↗