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Results for “genetic test utilization”

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PubMed2024

Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening.

PURPOSE: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

Humans↗

PubMed1998

Temporomandibular disorders: clinical and laboratory analyses for risk assessment of criteria for surgical therapy, a pilot study.

Temporomandibular disorder (TMD) is a broad category involving dysfunction of the skeletomuscular structures of the head and neck, and the temporomandibular joint (TMJ). A total of 66 patients, 54 with TMD, participated in this study. Group 1 (G1) had 31 patients suffering from early to intermediate stage disease, and no prior surgeries. G1 patients had arthrotomy/meniscectomy performed on the diseased joint(s). Group 2 (G2) consisted of 23 patients with late stage disease. All G2 patients had previously had unsuccessful TMJ surgery and were treated with either a partial or total joint prosthesis. Group 3 (G3) consisted of 12 patients who were clinically and radiographically asymptomatic. Medical histories including inflammatory bowel disease, headaches, vertigo, tinnitus and anemia, as well as surgical tonsillectomies, appendectomies and cholecystectomies, were significantly greater in G1 and G2 when compared to G3. Serological testing included HLA subtype, positive (ANA) antinuclear antibody, erythrocyte sedimentation rate (ESR), anemia profile, hormonal levels of prolactin and estradiol, and rheumatoid factor (RF). HLA frequencies, as well as some serological analyses, were significantly different among the three groups. These findings suggest that surgical failure may be secondary to autoimmune dysfunction with a predisposition to multisystem disease. The utilization of genetic markers, serological testing, and thorough medical and surgical histories should allow the clinician to determine which patients are potentially better surgical risk candidates for treatment of TMD.

Adolescent↗

PubMed2003

Awareness of genetic testing for increased cancer risk in the year 2000 National Health Interview Survey.

OBJECTIVES: This study explores factors associated with differential awareness of genetic tests for increased cancer risk in the US. METHODS: 27,405 respondents from the 2000 National Health Interview Survey, ages 25+, were asked if they had heard of these tests. RESULTS: 44.4% said 'yes', including 49.9% of whites, 32.9% of African-Americans, 32.3% of American Indians/Alaskan Natives, 28.0% of Asian/Pacific Islanders, and 20.6% of Hispanics. In multivariate analysis, test awareness was significantly associated with higher education, white race, age <60 years, female gender, private health insurance, personal or parent's history of certain cancers, physical activity, and vitamin/supplement use, among other factors. CONCLUSIONS: The survey showed which population subgroups may lack access to cancer genetics information and may therefore benefit from targeted strategies to ensure risk-appropriate utilization of genetic counseling and testing.

Adult↗

PubMed2006

Chronic dementing conditions, genomics, and new opportunities for nursing interventions.

PURPOSE: To (a) provide an overview of chronic dementing conditions; (b) discuss the etiologic and clinical characteristics of Alzheimer disease (AD) and Parkinson disease (PD) within the framework of the family systems genetic illness model; and (c) to explore opportunities to enhance outcomes through the integration of genomics information and technologies into nursing practice. DESIGN: An integrated review of the literature, including the organizing construct of the family systems genetic illness model. FINDINGS: AD and PD are both influenced by genetic and environmental factors; in a small percentage of families, gene mutations are the primary etiologic factor. Genetic testing is an option for some families experiencing early-onset, familial disease. Presymptomatic and diagnostic genetic testing have limited clinical utility for the more common late-onset AD and PD. CONCLUSIONS: The current abilities of healthcare professionals to effectively intervene in people with AD and PD are limited by an incomplete understanding of the biologic basis of these diseases. Advances in genomics research and technology are providing the information and tools necessary to understand the molecular basis of these devastating disorders toward the goal of more specific and effective interventions.

Alzheimer Disease↗

PubMed2004

The construction of a genetic linkage map of red raspberry (Rubus idaeus subsp. idaeus) based on AFLPs, genomic-SSR and EST-SSR markers.

Breeding in raspberry is time-consuming due to the highly heterozygous nature of this perennial fruit crop, coupled with relatively long periods of juvenility. The speed and precision of raspberry breeding can be improved by genetic linkage maps, thus facilitating the development of diagnostic markers for polygenic traits and the identification of genes controlling complex phenotypes. A genetic linkage map (789 cM) of the red raspberry Rubus idaeus has been constructed from a cross between two phenotypically different cultivars; the recent European cultivar Glen Moy and the older North American cultivar Latham. SSR markers were developed from both genomic and cDNA libraries from Glen Moy. These SSRs, together with AFLP markers, were utilised to create a linkage map. In order to test the utility of the genetic linkage map for QTL analysis, morphological data based on easily scoreable phenotypic traits were collected. The segregation of cane spininess, and the root sucker traits of density and spread from the mother plant, was quantified in two different environments. These traits were analysed for significant linkages to mapped markers using MapQTL and were found to be located on linkage group 2 for spines and group 8 for density and diameter. The availability of co-dominant markers allowed heterozygosities to be calculated for both cultivars.

Chromosome Mapping↗

PubMed2005

The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice.

Since its introduction almost 20 years ago, the tail suspension test has become one of the most widely used models for assessing antidepressant-like activity in mice. The test is based on the fact that animals subjected to the short-term, inescapable stress of being suspended by their tail, will develop an immobile posture. Various antidepressant medications reverse the immobility and promote the occurrence of escape-related behaviour. This review focuses on the utility this test as part of a research program aimed at understanding the mechanism of action of antidepressants. We discuss the inherent difficulties in modeling depression in rodents. We describe how the tail suspension differs from the closely related forced swim test. Further, we address some key issues associated with using the TST as a model of antidepressant action. We discuss issues regarding whether it satisfies criteria to be a valid model for assessing depression-related behavioural traits. We elaborate on the tests' ease of use, strain differences observed in the test and gender effects in the test. We focus on the utility of the test for genetic analysis. Furthermore, we discuss the concept of whether immobility maybe a behavioural trait relevant to depression. All of the available pharmacological data using the test in genetically modified mice is collated. Special attention is given to selective breeding programs such as the Rouen 'depressed' mice which have been bred for high and low immobility in the tail suspension test. We provide an extensive pooling of the pharmacological studies published to date using the test. Finally, we provide novel pharmacological validation of an automated system (Bioseb) for assessing immobility. Taken together, we conclude that the tail suspension test is a useful test for assessing the behavioural effects of antidepressant compounds and other pharmacological and genetic manipulations relevant to depression.

Analysis of Variance↗

PubMed2006

Plasmid pWW115, a cloning vector for use with Moraxella catarrhalis.

The plasmid shuttle vector pWW102B is able to replicate in only a modest number of Moraxella catarrhalis strains. Plasmid pWW115, a spontaneous deletion mutant of pWW102B, was shown to lack both the pACYC184-derived origin of replication and the associated chloramphenicol-resistance gene but was able to replicate in every M. catarrhalis strain tested in this study, including one strain that had been previously refractory to all types of genetic manipulations. To test the utility of this plasmid, a M. catarrhalis gene encoding the UspA2 serum-resistance factor was cloned into pWW115 and the resultant recombinant plasmid was shown to confer serum-resistance on a serum-sensitive M. catarrhalis uspA2 mutant.

Bacterial Outer Membrane Proteins↗

PubMed1997

Long-term impact of Huntington disease linkage testing.

We performed a long-term follow-up of Huntington disease (HD) predictive testing (an average of 6 years post-test) for 16 of 20 people who received informative linkage test results. Although no pre-test or baseline psychological differences were noted between those with an increased versus a decreased risk of HD, the long-term impact was dramatically different in these two groups. The low-risk group reported less uncertainty, anxiety or worry, fear, and worry about children's risk, whereas the high-risk group reported either the same or increased concern in these areas. Those at low risk also acknowledged an increased sense of control and self-esteem, whereas those at high risk reported decreases or no changes. One high-risk individual reported chronic depression that had occurred since the testing. Additionally, those at low risk reported greater reliance and faith in spiritual or religious beliefs than those at high risk. The emotional impact of HD genetic testing justifies the continued utilization of pre- and post-test counseling protocols. Pre-test counseling should include discussion of the known risks and benefits of predictive testing, with special emphasis on the participant's expectations for future change and improvement. Although the psychological impact appears mostly favorable for those with decreased risk, there is risk for a decline in psychological well-being over time for those with an increased risk for HD.

Adult↗

PubMed2005

Two-sample tests for comparing intra-individual genetic sequence diversity between populations.

Consider a study of two groups of individuals infected with a population of a genetically related heterogeneous mixture of viruses, and multiple viral sequences are sampled from each person. Based on estimates of genetic distances between pairs of aligned viral sequences within individuals, we develop four new tests to compare intra-individual genetic sequence diversity between the two groups. This problem is complicated by two levels of dependency in the data structure: (i) Within an individual, any pairwise distances that share a common sequence are positively correlated; and (ii) for any two pairings of individuals which share a person, the two differences in intra-individual distances between the paired individuals are positively correlated. The first proposed test is based on the difference in mean intra-individual pairwise distances pooled over all individuals in each group, standardized by a variance estimate that corrects for the correlation structure using U-statistic theory. The second procedure is a nonparametric rank-based analog of the first test, and the third test contrasts the set of subject-specific average intra-individual pairwise distances between the groups. These tests are very easy to use and solve correlation problem (i). The fourth procedure is based on a linear combination of all possible U-statistics calculated on independent, identically distributed sequence subdatasets, over the two levels (i) and (ii) of dependencies in the data, and is more complicated than the other tests but can be more powerful. Although the proposed methods are empirical and do not fully utilize knowledge from population genetics, the tests reflect biology through the evolutionary models used to derive the pairwise sequence distances. The new tests are evaluated theoretically and in a simulation study, and are applied to a dataset of 200 HIV sequences sampled from 21 children.

Base Sequence↗

PubMed2002

[The development and clinical implication of genetic tests].

Genetic testing is not performed as often as other clinical laboratory tests currently available. However, physicians will in the future be eager to analyze and diagnose the diseases at a genetic level, since the DNA sequence analysis of the human genome has been completed. Moreover, information on single nucleotide polymorphisms in disease susceptibility and drug responsiveness is increasing, and genetic testing based on this information will be utilized for the prevention of disease and order-made medicine. Hence, the demand for genetic tests will increase in the near future. In this review, the development and clinical implication of genetic tests will be discussed.

Disease Susceptibility↗

PubMed1994

Preferences of pregnant women for amniocentesis or chorionic villus sampling for prenatal testing: comparison of patients' choices and those of a decision-analytic model.

Decision analytic models have suggested that the choice of amniocentesis or chorionic villus sampling for prenatal genetic testing is a utility-driven decision. We compared preferences for prenatal testing among 156 pregnant women who had chosen either amniocentesis (n = 82) or chorionic villus sampling (n = 74) for the indication of maternal age. We also compared their choices with those of a decision-analytic model based on their preferences, and age-specific rates of spontaneous abortion and chromosomal abnormalities. Preferences were assessed using written scenarios describing potential outcomes of prenatal testing, and were recorded on linear rating scales. The differences in preference ratings for first- vs second-trimester prenatal diagnosis of a normal child (4.2 vs -1.6, p = 0.0004), and for first- vs second-trimester abortion of an abnormal fetus (4.4 vs -1.6, p = 0.01), were significantly greater among women choosing chorionic villus sampling than among women choosing amniocentesis. There were no significant differences between chorionic villus sampling and amniocentesis patients in their preference ratings for test-related miscarriage, disconfirmed results at pregnancy termination, or maternal morbidity from therapeutic abortion. After adjusting for demographic and obstetric factors, the difference in preferences for early vs late prenatal diagnosis was an independent predictor of the choice of chorionic villus sampling in a multivariate model. Among women whose decision analyses selected amniocentesis, 56.8% had chosen amniocentesis, and among women whose analyses selected chorionic villus sampling, 63.2% had chosen chorionic villus sampling (p = 0.05). We conclude that the preferences of pregnant women for the outcomes of prenatal testing were associated with their choice of amniocentesis or chorionic villus sampling. In addition, the choice of prenatal test made by the majority of women was concordant with that of a decision-analytic model that incorporated their preferences. Nevertheless, because many women made choices that were discordant with their decision-analytic results, further research into the bases for their choices is warranted.

Abortion, Induced↗

PubMed2003

Clinical utility and outcome of HFE-genotyping in the search for hereditary hemochromatosis.

BACKGROUND: Hereditary hemochromatosis (HH), a disease involving iron accumulation in internal organs, occurs in about 1 in 200-400 Caucasians. The gene mutated in this disorder is termed HFE. The present study was designed to evaluate the diagnostic utility and outcome of genetic testing for HH in the service of public health care. METHODS: 137 subjects were referred by health clinics and general hospitals for HFE genotyping from various parts of Finland during the period 1999-2001. Two major mutations (C282Y and H63D) were determined for each patient. Reasons contributing to referrals and sets of values for serum transferrin saturation (s-TS) and iron and ferritin concentrations were also determined. RESULTS: 16.8% of the subjects were homozygous for the C282Y mutation, together with seven C282Y/H63D compound heterozygotes (5.1%). The rate of positive findings for the most typical mutations responsible for HH was found to have increased steadily during the period 1999-2001. CONCLUSIONS: Our data support a role for active testing for the C282Y and H63D mutations in health care. The fairly low number of genotyping requests nevertheless suggests that a large number of patients even with typical clinical signs or symptoms continue to escape detection.

Adult↗

PubMed1992

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Alleles↗

PubMed1999

Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors.

The activation state of beta-adrenergic receptors (beta-ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metabolic rate. In order to achieve homeostasis in vivo, the cellular signals generated by beta-AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic knockout models to test directly the role of beta1- and/or beta2-AR expression on these homeostatic control mechanisms. Despite total absence of beta1- and beta2-ARs, the predominant cardiovascular beta-adrenergic subtypes, basal heart rate, blood pressure, and metabolic rate do not differ from wild type controls. However, stimulation of beta-AR function by beta-AR agonists or exercise reveals significant impairments in chronotropic range, vascular reactivity, and metabolic rate. Surprisingly, the blunted chronotropic and metabolic response to exercise seen in beta1/beta2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single beta1- and beta2-AR knockouts as well as the beta1-/beta2-AR double knock-out suggest that in the mouse, beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular beta3-AR responsiveness are also observed in beta1-/beta2-AR double knockouts. In addition to its ability to define beta-AR subtype-specific functions, this genetic approach is also useful in identifying adaptive alterations that serve to maintain critical physiological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed.

Animals↗

PubMed2006

A polymorphism in the 5'-untranslated region of the porcine cholecystokinin type a receptor gene affects feed intake and growth.

The location and utilization of quantitative trait loci (QTL) and candidate genes with significant effects on economically important traits are becoming increasingly important in livestock breeding programs. The porcine cholecystokinin type A receptor (CCKAR) is a candidate gene for performance traits, due to its known role in the physiological control of feed intake, satiety, and obesity. We investigated the association of CCKAR polymorphisms with feeding, growth, and efficiency traits in an F2 population derived from a cross between Meishan and Large White founder animals and in lines of Large White pigs that had been divergently selected on the basis of lean growth efficiency traits. In the F2 population, CCKAR genotype was significantly associated with daily feed intake and average daily gain. The effects of the polymorphisms were then assessed in a larger-scale analysis of segregating commercial lines. A newly discovered single-nucleotide polymorphism (SNP) within the 5'-untranslated region (5'-UTR) had highly significant effects on feed intake, average daily gain, and days to 110 kg, which were not seen for a previously reported SNP within the CCKAR gene. Furthermore, we provide evidence that the novel SNP disrupts the binding of the YY1 transcription factor, which raises the possibility that it is the causal variant. The 5'-UTR SNP could be utilized as a molecular genetic test for increased feed intake, faster lean growth, and reduced days to market weight in segregating commercial lines.

5' Untranslated Regions↗

PubMed1996

Using genetic information: the individual and the community.

Genetic information is both individual and communal (species and family). Responsible use of this information requires exploration of a proper relationship between individual and communal values, rights, needs and decision-making. The individual/community issue is also important for dealing with the differences of emphasis between Western and non-Western cultures in this regard. Non-Western cultures emphasize community but also value the individual, while Western cultures know extreme individualism is counter-productive. This paper will discuss the individual-community relationship as it impacts on various problem areas in the utilization of genetic information, e.g. test results which impact family as well as individuals and which impact institutional projected costs while also making problematic individual access to employment, insurance and health care. The paper will also address the pernicious import of the paradigm of genetic essentialism which exaggerates individual responsibility while neglecting institutional and communal responsibility in genetic matters.

Culture↗

PubMed1985

A covariance structure model for quantitative genetic research.

In this paper, we have presented a general covariance structure model for quantitative genetic research that incorporates measurement theory, components of variance, and regression theory for specification of structural relations among variance components. Each portion of the general model addresses specific issues important in delineating the genetic etiology of continuous traits. Through specification of a measurement model, genetic and environmental influences can be estimated independently of measurement error. Genetic and environmental sources of variance are defined from familial sampling designs through the components of variance model. Structural relationships among several traits at the genetic or environmental level can be specified through the regression model. The significance of parameters specified in each part of the model can be tested through model comparisons using a likelihood ratio chi-square test. We utilized the general model to test genetic covariance as a source of observed covariation of obesity and glucose tolerance in the Pima Indians. We initially applied the modeling approach using full-sib, half-sib sampling among the Pima with a second application including offspring as well as parental scores. Our initial applications of the methodology suggest that the covariance structure model can be a useful tool in genetic epidemiological research. Through model comparisons, our findings suggest that the association of glucose tolerance and obesity in the Pima is not due to a common set of genes but rather due to non-familial environmental influences. In conclusion, one task important for future research, as we see it, is the application of covariance structure models to other familial sampling designs and the evaluation of the usefulness of this approach through further applications to data.

Arizona↗

PubMed2005

From genetics to genomics: using gene-based medicine to prevent disease and promote health in children.

The remarkable achievements of the Human Genome Project promise great opportunities for disease prediction, treatment, and prevention. In this paper, we discuss the continuum of genetic variation as medical practice begins to shift focus from the study of single genes (genetics) to the study of the entire genome (genomics). Pediatricians should anticipate an influx of genetic information and will need to become as facile in interpreting this type of predictive information as they are with other types of medical data, while recognizing the unique ethical, legal, and social implications of genetic testing in children. We discuss an approach to assist pediatricians in decision-making that emphasizes the need for knowledge about the analytic performance of genetic tests, their validity in predicting health outcomes, and the utility of the genetic information in improving health and preventing disease.

Adolescent↗