Genetic influence on athletic performance

PubMed Central

Guth, Lisa M.; Roth, Stephen M.

2014-01-01

Purpose of review The purpose of this review is to summarize the existing literature on the genetics of athletic performance, with particular consideration for the relevance to young athletes. Recent findings Two gene variants, ACE I/D and ACTN3 R577X, have been consistently associated with endurance (ACE I/I) and power-related (ACTN3 R/R) performance, though neither can be considered predictive. The role of genetic variation in injury risk and outcomes is more sparsely studied, but genetic testing for injury susceptibility could be beneficial in protecting young athletes from serious injury. Little information on the association of genetic variation with athletic performance in young athletes is available; however, genetic testing is becoming more popular as a means of talent identification. Despite this increase in the use of such testing, evidence is lacking for the usefulness of genetic testing over traditional talent selection techniques in predicting athletic ability, and careful consideration should be given to the ethical issues surrounding such testing in children. Summary A favorable genetic profile, when combined with an optimal training environment, is important for elite athletic performance; however, few genes are consistently associated with elite athletic performance, and none are linked strongly enough to warrant their use in predicting athletic success. PMID:24240283

Ethical issues in predictive genetic testing: a public health perspective.

PubMed

Fulda, K G; Lykens, K

2006-03-01

As a result of the increase in genetic testing and the fear of discrimination by insurance companies, employers, and society as a result of genetic testing, the disciplines of ethics, public health, and genetics have converged. Whether relatives of someone with a positive predictive genetic test should be notified of the results and risks is a matter urgently in need of debate. Such a debate must encompass the moral and ethical obligations of the diagnosing physician and the patient. The decision to inform or not will vary depending on what moral theory is used. Utilising the utilitarian and libertarian theories produces different outcomes. The principles of justice and non-maleficence will also play an important role in the decision.

Ethical issues in predictive genetic testing: a public health perspective

PubMed Central

Fulda, K G; Lykens, K

2006-01-01

As a result of the increase in genetic testing and the fear of discrimination by insurance companies, employers, and society as a result of genetic testing, the disciplines of ethics, public health, and genetics have converged. Whether relatives of someone with a positive predictive genetic test should be notified of the results and risks is a matter urgently in need of debate. Such a debate must encompass the moral and ethical obligations of the diagnosing physician and the patient. The decision to inform or not will vary depending on what moral theory is used. Utilising the utilitarian and libertarian theories produces different outcomes. The principles of justice and non‐maleficence will also play an important role in the decision. PMID:16507657

The challenge of developmentally appropriate care: predictive genetic testing in young people for familial adenomatous polyposis.

PubMed

Duncan, Rony E; Gillam, Lynn; Savulescu, Julian; Williamson, Robert; Rogers, John G; Delatycki, Martin B

2010-03-01

Predictive genetic tests for familial adenomatous polyposis (FAP) are routinely offered to young people during early adolescence. While this is not controversial, due to the medical benefit conferred by the test, it is nonetheless challenging as a consequence of the stage of life of the young people, and the simultaneous involvement of multiple family members. Despite these challenges, it is possible to ensure that the test is offered in such a way that it actively acknowledges and facilitates young people's developing autonomy and psychosocial well-being. In this paper we present findings from ten in-depth interviews with young people who have undergone predictive genetic testing for FAP (four male, six female; five gene-positive, five gene-negative; aged 10-17 years at the time of their predictive test; aged 12-25 years at the time of their research interview). We present five themes that emerged from the interviews which highlight key ethical challenges associated with such testing. These are: (1) the significance of the test; (2) young people's lack of involvement in the decision to be tested; (3) young people's limited understanding; (4) provision of the blood test at the first visit; and (5) group testing of family members. We draw on these themes to make eight recommendations for future practice. Together, these recommendations highlight the importance of providing developmentally appropriate care to young people undergoing predictive genetic testing for FAP.

Ethical dilemmas in genetic testing: examples from the Cuban program for predictive diagnosis of hereditary ataxias.

PubMed

Mariño, Tania Cruz; Armiñán, Rubén Reynaldo; Cedeño, Humberto Jorge; Mesa, José Miguel Laffita; Zaldivar, Yanetza González; Rodríguez, Raúl Aguilera; Santos, Miguel Velázquez; Mederos, Luis Enrique Almaguer; Herrera, Milena Paneque; Pérez, Luis Velázquez

2011-06-01

Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities.

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

PubMed

Paynter, Nina P; Ridker, Paul M; Chasman, Daniel I

2016-02-19

In this review, we lay out 3 areas currently being evaluated for incorporation of genetic information into clinical practice related to atherosclerosis. The first, familial hypercholesterolemia, is the clearest case for utility of genetic testing in diagnosis and potentially guiding treatment. Already in use for confirmatory testing of familial hypercholesterolemia and for cascade screening of relatives, genetic testing is likely to expand to help establish diagnoses and facilitate research related to most effective therapies, including new agents, such as PCSK9 inhibitors. The second area, adding genetic information to cardiovascular risk prediction for primary prevention, is not currently recommended. Although identification of additional variants may add substantially to prediction in the future, combining known variants has not yet demonstrated sufficient improvement in prediction for incorporation into commonly used risk scores. The third area, pharmacogenetics, has utility for some therapies today. Future utility for pharmacogenetics will wax or wane depending on the nature of available drugs and therapeutic strategies. © 2016 American Heart Association, Inc.

The future in clinical genetics: affective forecasting biases in patient and clinician decision making.

PubMed

Peters, S A; Laham, S M; Pachter, N; Winship, I M

2014-04-01

When clinicians facilitate and patients make decisions about predictive genetic testing, they often base their choices on the predicted emotional consequences of positive and negative test results. Research from psychology and decision making suggests that such predictions may often be biased. Work on affective forecasting-predicting one's future emotional states-shows that people tend to overestimate the impact of (especially negative) emotional events on their well-being; a phenomenon termed the impact bias. In this article, we review the causes and consequences of the impact bias in medical decision making, with a focus on applying such findings to predictive testing in clinical genetics. We also recommend strategies for reducing the impact bias and consider the ethical and practical implications of doing so. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Experience, knowledge, and opinions about childhood genetic testing in Batten disease.

PubMed

Adams, Heather R; Rose, Katherine; Augustine, Erika F; Kwon, Jennifer M; deBlieck, Elisabeth A; Marshall, Frederick J; Vierhile, Amy; Mink, Jonathan W; Nance, Martha A

2014-02-01

Policies for genetic testing in children (GTIC) focus on medical or psychosocial benefit to the child, discouraging or prohibiting carrier testing, and advising caution regarding pre-symptomatic diagnosis if no treatment exists. This study sought to understand parents' perspectives on these issues and determine their experiences and knowledge related to genetic testing for Batten disease - a set of inherited neurodegenerative diseases of childhood onset for which no disease modifying therapies yet exist. Parents of children with Batten disease completed a survey of their knowledge of genetics, experience with genetic testing, and opinions regarding GTIC. 54% had sought genetic testing for non-affected family members, including predictive diagnosis of healthy, at-risk children. Participation in any genetic counseling was associated with greater knowledge on questions about genetics. The majority of parents felt it was better to know ahead of time that a child would develop Batten disease, believed that this knowledge would not alter how they related to their child, and that parents should have the final say in deciding whether to obtain GTIC. Parents of children with an inherited disease are knowledgeable about genetics and wish to establish predictive or carrier status of at-risk children. Copyright © 2013 Elsevier Inc. All rights reserved.

Genetic testing in the epilepsies—Report of the ILAE Genetics Commission

PubMed Central

Ottman, Ruth; Hirose, Shinichi; Jain, Satish; Lerche, Holger; Lopes-Cendes, Iscia; Noebels, Jeffrey L.; Serratosa, José; Zara, Federico; Scheffer, Ingrid E.

2010-01-01

SUMMARY In this report, the International League Against Epilepsy (ILAE) Genetics Commission discusses essential issues to be considered with regard to clinical genetic testing in the epilepsies. Genetic research on the epilepsies has led to the identification of more than 20 genes with a major effect on susceptibility to idiopathic epilepsies. The most important potential clinical application of these discoveries is genetic testing: the use of genetic information, either to clarify the diagnosis in people already known or suspected to have epilepsy (diagnostic testing), or to predict onset of epilepsy in people at risk because of a family history (predictive testing). Although genetic testing has many potential benefits, it also has potential harms, and assessment of these potential benefits and harms in particular situations is complex. Moreover, many treating clinicians are unfamiliar with the types of tests available, how to access them, how to decide whether they should be offered, and what measures should be used to maximize benefit and minimize harm to their patients. Because the field is moving rapidly, with new information emerging practically every day, we present a framework for considering the clinical utility of genetic testing that can be applied to many different syndromes and clinical contexts. Given the current state of knowledge, genetic testing has high0020clinical utility in few clinical contexts, but in some of these it carries implications for daily clinical practice. PMID:20100225

State of play in direct-to-consumer genetic testing for lifestyle-related diseases: market, marketing content, user experiences and regulation.

PubMed

Saukko, Paula

2013-02-01

Direct-to-consumer (DTC) genetic tests have aroused controversy. Critics have argued many of the tests are not backed by scientific evidence, misguide their customers and should be regulated more stringently. Proponents suggest that finding out genetic susceptibilities for diseases could encourage healthier behaviours and makes the results of genetics research available to the public. This paper reviews the state of play in DTC genetic testing, focusing on tests identifying susceptibilities for lifestyle-related diseases. It will start with mapping the market for the tests. The paper will review (1) research on the content of the online marketing of DTC tests, (2) studies on the effects of DTC genetic tests on customers and (3) academic and policy proposals on how to regulate the tests. Current studies suggest that the marketing of DTC genetic tests often exaggerates their predictive powers, which could misguide consumers. However, research indicates that the tests do not seem to have major negative effects (worry and confusion) but neither do they engender positive effects (lifestyle change) on current users. Research on regulation of the tests has most commonly suggested regulating the marketing claims of the companies. In conclusion, the risks and benefits of DTC genetic tests are less significant than what has been predicted by critics and proponents, which will be argued reflects broader historical trends transforming health and medicine.

Genome-based prediction of test cross performance in two subsequent breeding cycles.

PubMed

Hofheinz, Nina; Borchardt, Dietrich; Weissleder, Knuth; Frisch, Matthias

2012-12-01

Genome-based prediction of genetic values is expected to overcome shortcomings that limit the application of QTL mapping and marker-assisted selection in plant breeding. Our goal was to study the genome-based prediction of test cross performance with genetic effects that were estimated using genotypes from the preceding breeding cycle. In particular, our objectives were to employ a ridge regression approach that approximates best linear unbiased prediction of genetic effects, compare cross validation with validation using genetic material of the subsequent breeding cycle, and investigate the prospects of genome-based prediction in sugar beet breeding. We focused on the traits sugar content and standard molasses loss (ML) and used a set of 310 sugar beet lines to estimate genetic effects at 384 SNP markers. In cross validation, correlations >0.8 between observed and predicted test cross performance were observed for both traits. However, in validation with 56 lines from the next breeding cycle, a correlation of 0.8 could only be observed for sugar content, for standard ML the correlation reduced to 0.4. We found that ridge regression based on preliminary estimates of the heritability provided a very good approximation of best linear unbiased prediction and was not accompanied with a loss in prediction accuracy. We conclude that prediction accuracy assessed with cross validation within one cycle of a breeding program can not be used as an indicator for the accuracy of predicting lines of the next cycle. Prediction of lines of the next cycle seems promising for traits with high heritabilities.

A systematic review of the factors associated with interest in predictive genetic testing for obesity, type II diabetes and heart disease.

PubMed

Collins, J; Ryan, L; Truby, H

2014-10-01

In the future, it may be possible for individuals to take a genetic test to determine their genetic predisposition towards developing lifestyle-related chronic diseases. A systematic review of the literature was undertaken to identify the factors associated with an interest in having predictive genetic testing for obesity, type II diabetes and heart disease amongst unaffected adults. Ovid Medline, PsycINFO and EMBASE online databases were searched using predefined search terms. Publications meeting the inclusion criteria (English language, free-living adult population not selected as a result of their disease diagnosis, reporting interest as an outcome, not related to a single gene inherited disease) were assessed for quality and content. Narrative synthesis of the results was undertaken. From the 2329 publications retrieved, eight studies met the inclusion criteria and were included in the review. Overall, the evidence base was small but of positive quality. Interest was associated with personal attitudes towards disease risk and the provision of information about genetic testing, shaped by perceived risk of disease and expected outcomes of testing. The role of demographic factors was investigated with largely inconclusive findings. Interest in predictive genetic testing for obesity, type II diabetes or heart disease was greatest amongst those who perceived the risk of disease to be high and/or the outcomes of testing to be beneficial. © 2013 The British Dietetic Association Ltd.

[Willingness of Students of Economics to Pay for Predictive Oncological Genetic Testing - An Empirical Analysis].

PubMed

Siol, V; Lange, A; Prenzler, A; Neubauer, S; Frank, M

2017-05-01

Objectives: The present study aims to investigate the interest of young adults in predictive oncological genetic testing and their willingness to pay for such a test. Furthermore, major determinants of the 2 variables of interest were identified. Methods: 348 students of economics from the Leibniz University of Hanover were queried in July 2013 using an extensive questionnaire. Among other things, the participants were asked if they are interested in information about the probability to develop cancer in the future and their willingness to pay for such information. Data were analysed using descriptive statistics and ordinal probit regressions. Additionally marginal effects were calculated. Results: About 50% of the students were interested in predictive oncological genetic testing and were willing to pay for the test. Moreover, the participants who were willing to pay for the test partly attach high monetary values to the information that could so be obtained. The study shows that the interest of the students and their willingness to pay were primarily influenced by individual attitudes and perceptions. Conclusions: The study proves that young adults were interested in predictive genetic testing and appreciate information about their probability of develop cancer someday. © Georg Thieme Verlag KG Stuttgart · New York.

Genetic-based prediction of disease traits: prediction is very difficult, especially about the future†

PubMed Central

Schrodi, Steven J.; Mukherjee, Shubhabrata; Shan, Ying; Tromp, Gerard; Sninsky, John J.; Callear, Amy P.; Carter, Tonia C.; Ye, Zhan; Haines, Jonathan L.; Brilliant, Murray H.; Crane, Paul K.; Smelser, Diane T.; Elston, Robert C.; Weeks, Daniel E.

2014-01-01

Translation of results from genetic findings to inform medical practice is a highly anticipated goal of human genetics. The aim of this paper is to review and discuss the role of genetics in medically-relevant prediction. Germline genetics presages disease onset and therefore can contribute prognostic signals that augment laboratory tests and clinical features. As such, the impact of genetic-based predictive models on clinical decisions and therapy choice could be profound. However, given that (i) medical traits result from a complex interplay between genetic and environmental factors, (ii) the underlying genetic architectures for susceptibility to common diseases are not well-understood, and (iii) replicable susceptibility alleles, in combination, account for only a moderate amount of disease heritability, there are substantial challenges to constructing and implementing genetic risk prediction models with high utility. In spite of these challenges, concerted progress has continued in this area with an ongoing accumulation of studies that identify disease predisposing genotypes. Several statistical approaches with the aim of predicting disease have been published. Here we summarize the current state of disease susceptibility mapping and pharmacogenetics efforts for risk prediction, describe methods used to construct and evaluate genetic-based predictive models, and discuss applications. PMID:24917882

Genetic Testing in Psychiatry: A Review of Attitudes and Beliefs

PubMed Central

Lawrence, Ryan E; Appelbaum, Paul S.

2012-01-01

The advent of genetic testing for psychiatric conditions raises difficult questions about when and how the tests should be used. Development of policies regarding these issues may be informed in a variety of ways by the views of key stakeholders: patients, family members, healthcare professionals, and the general public. Here we review empirical studies of attitudes towards genetic testing among these groups. Patients and family members show strong interest in diagnostic and predictive genetic testing, and to a considerable extent psychiatrists share their enthusiasm. Prenatal test utilization seems likely to depend both on parental views on abortion and the seriousness of the disorder. Parents show a surprising degree of interest in predictive testing of children, even when there are no preventive interventions available. Many persons report themselves ready to alter their lifestyles and plans for marriage and family in response to test results. Respondents also fear negative consequences, from discrimination to being unable to cope with knowledge of their “genetic fate.” Empirical studies of beliefs about genetic testing suggest tests are likely to be embraced widely, but the studies have methodologic limitations, reducing the certainty of their conclusions, and indicating a need for further research with more representative samples. PMID:22168293

Apocalypse...now? Molecular epidemiology, predictive genetic tests, and social communication of genetic contents.

PubMed

Castiel, L D

1999-01-01

The author analyzes the underlying theoretical aspects in the construction of the molecular watershed of epidemiology and the concept of genetic risk, focusing on issues raised by contemporary reality: new technologies, globalization, proliferation of communications strategies, and the dilution of identity matrices. He discusses problems pertaining to the establishment of such new interdisciplinary fields as molecular epidemiology and molecular genetics. Finally, he analyzes the repercussions of the social communication of genetic content, especially as related to predictive genetic tests and cloning of animals, based on triumphal, deterministic metaphors sustaining beliefs relating to the existence and supremacy of concepts such as 'purity', 'essence', and 'unification' of rational, integrated 'I's/egos'.

Commercial Genetic Testing and Its Governance in Chinese Society

ERIC Educational Resources Information Center

Sui, Suli; Sleeboom-Faulkner, Margaret

2015-01-01

This paper provides an empirical account of commercial genetic testing in China. Commercial predictive genetic testing has emerged and is developing rapidly in China, but there is no strict and effective governance. This raises a number of serious social and ethical issues as a consequence of the enormous potential market for such tests. The paper…

Genetic change and rates of cladogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Avise, J.C.; Ayala, F.J.

1975-12-01

Models are introduced which predict ratios of mean levels of genetic divergence in species-rich versus species-poor phylads under two competing assumptions: (1) genetic differentiation is a function of time, unrelated to the number of cladogenetic events and (2) genetic differentiation is proportional to the number of speciation events in the group. The models are simple, general, and biologically real, but not precise. They lead to qualitatively distinct predictions about levels of genetic divergence depending upon the relationship between rates of speciation and amount of genetic change. When genetic distance between species is a function of time, mean genetic distances inmore » speciose and depauperate phylads of equal evolutionary age are very similar. On the contrary, when genetic distance is a function of the number of speciations in the history of a phylad, the ratio of mean genetic distances separating species in speciose versus depauperate phylads is greater than one, and increases rapidly as the frequency of speciations in one group relative to the other increases. The models may be tested with data from natural populations to assess (1) possible correlations between rates of anagenesis and cladogenesis and (2) the amount of genetic differentiation accompanying the speciation process. The data collected in electrophoretic surveys and other kinds of studies can be used to test the predictions of the models. For this purpose genetic distances need to be measured in speciose and depauperate phylads of equal evolutionary age. The limited information presently available agrees better with the model predicting that genetic change is primarily a function of time, and is not correlated with rates of speciation. Further testing of the models is, however, required before firm conclusions can be drawn. (auth)« less

Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value.

PubMed

Mathews, Rebecca; Hall, Wayne; Carter, Adrian

2012-12-01

Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non-consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

[Diabetes and predictive medicine--parallax of the present time].

PubMed

Rybka, J

2010-04-01

Predictive genetics uses genetic testing to estimate the risk in asymptomatic persons. Since in the case of multifactorial diseases predictive genetic analysis deals with findings which allow wider interpretation, it has a higher predictive value in expressly qualified diseases (monogenous) with high penetration compared to multifactorial (polygenous) diseases with high participation of environmental factors. In most "civilisation" (multifactorial) diseases including diabetes, heredity and environmental factors do not play two separate, independent roles. Instead, their interactions play a principal role. The new classification of diabetes is based on the implementation of not only ethiopathogenetic, but also genetic research. Diabetes mellitus type 1 (DM1T) is a polygenous multifactorial disease with the genetic component carrying about one half of the risk, the non-genetic one the other half. The study of the autoimmune nature of DM1T in connection with genetic analysis is going to bring about new insights in DM1T prediction. The author presents new pieces of knowledge on molecular genetics concerning certain specific types of diabetes. Issues relating to heredity in diabetes mellitus type 2 (DM2T) are even more complex. The disease has a polygenous nature, and the phenotype of a patient with DM2T, in addition to environmental factors, involves at least three, perhaps even tens of different genetic variations. At present, results at the genom-wide level appear to be most promising. The current concept of prediabetes is a realistic foundation for our prediction and prevention of DM2T. A multifactorial, multimarker approach based on our understanding of new pathophysiological factors of DM2T, tries to outline a "map" of prediabetes physiology, and if these tests are combined with sophisticated methods of genetic forecasting of DM2T, this may represent a significant step in our methodology of diabetes prediction. So far however, predictive genetics is limited by the interpretation of genetic predisposition and individualisation of the level of risk. There is no doubt that interpretation calls for co-operation with clinicians, while results of genetic analyses should presently be not uncritically overestimated. Predictive medicine, however, unquestionably fulfills the preventive focus of modern medicine, and genetic analysis is a perspective diagnostic method.

Experience, Knowledge, and Opinions about Childhood Genetic Testing in Batten Disease

PubMed Central

Rose, Katherine; Augustine, Erika F.; Kwon, Jennifer M.; deBlieck, Elisabeth A.; Marshall, Frederick J.; Vierhile, Amy; Mink, Jonathan W.; Nance, Martha A.

2013-01-01

Background and Objectives Policies for genetic testing in children (GTIC) focus on medical or psychosocial benefit to the child, discouraging or prohibiting carrier testing, and advising caution regarding pre-symptomatic diagnosis if no treatment exists. This study sought to understand parents’ perspectives on these issues and determine their experiences and knowledge related to genetic testing for Batten disease – a set of inherited neurodegenerative diseases of childhood onset for which no disease modifying therapies yet exist. Methods Parents of children with Batten disease completed a survey of their knowledge of genetics, experience with genetic testing, and opinions regarding GTIC. Results 54% had sought genetic testing for non-affected family members, including predictive diagnosis of healthy, at-risk children. Participation in any genetic counseling was associated with greater knowledge on questions about genetics. The majority of parents felt it was better to know ahead of time that a child would develop Batten disease, believed that this knowledge would not alter how they related to their child, and that parents should have the final say in deciding whether to obtain GTIC. Conclusions Parents of children with an inherited disease are knowledgeable about genetics and wish to establish predictive or carrier status of at-risk children. PMID:24246680

A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

PubMed

Adar, Tomer; Rodgers, Linda H; Shannon, Kristen M; Yoshida, Makoto; Ma, Tianle; Mattia, Anthony; Lauwers, Gregory Y; Iafrate, Anthony J; Chung, Daniel C

2017-03-01

To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P<0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.

Counseling Psychology in the Era of Genetic Testing: Considerations for Practice, Research, and Training

ERIC Educational Resources Information Center

Kaut, Kevin P.

2006-01-01

The field of genetics and the process of testing for genetic disorders have advanced considerably over the past half century, ushering in significant improvements in certain areas of medical diagnosis and disease prediction. However, genetic discoveries are accompanied by many social, emotional, and psychological implications, and counseling…

The clinical application of genetic testing in type 2 diabetes: a patient and physician survey.

PubMed

Grant, R W; Hivert, M; Pandiscio, J C; Florez, J C; Nathan, D M; Meigs, J B

2009-11-01

Advances in type 2 diabetes genetics have raised hopes that genetic testing will improve disease prediction, prevention and treatment. Little is known about current physician and patient views regarding type 2 diabetes genetic testing. We hypothesised that physician and patient views would differ regarding the impact of genetic testing on motivation and adherence. We surveyed a nationally representative sample of US primary care physicians and endocrinologists (n = 304), a random sample of non-diabetic primary care patients (n = 152) and patients enrolled in a diabetes pharmacogenetics study (n = 89). Physicians and patients favoured genetic testing for diabetes risk prediction (79% of physicians vs 80% of non-diabetic patients would be somewhat/very likely to order/request testing, p = 0.7). More patients than physicians (71% vs 23%, p < 0.01) indicated that a 'high risk' result would be very likely to improve motivation to adopt preventive lifestyle changes. Patients favoured genetic testing to guide therapy (78% of patients vs 48% of physicians very likely to request/recommend testing, p < 0.01) and reported that genetic testing would make them 'much more motivated' to adhere to medications (72% vs 18% of physicians, p < 0.01). Many physicians (39%) would be somewhat/very likely to order genetic testing before published evidence of clinical efficacy. Despite the paucity of current data, physicians and patients reported high expectations that genetic testing would improve patient motivation to adopt key behaviours for the prevention or control of type 2 diabetes. This suggests the testable hypothesis that 'genetic' risk information might have greater value to motivate behaviour change compared with standard risk information.

Predictive genetic testing in minors for late-onset conditions: a chronological and analytical review of the ethical arguments.

PubMed

Mand, Cara; Gillam, Lynn; Delatycki, Martin B; Duncan, Rony E

2012-09-01

Predictive genetic testing is now routinely offered to asymptomatic adults at risk for genetic disease. However, testing of minors at risk for adult-onset conditions, where no treatment or preventive intervention exists, has evoked greater controversy and inspired a debate spanning two decades. This review aims to provide a detailed longitudinal analysis and concludes by examining the debate's current status and prospects for the future. Fifty-three relevant theoretical papers published between 1990 and December 2010 were identified, and interpretative content analysis was employed to catalogue discrete arguments within these papers. Novel conclusions were drawn from this review. While the debate's first voices were raised in opposition of testing and their arguments have retained currency over many years, arguments in favour of testing, which appeared sporadically at first, have gained momentum more recently. Most arguments on both sides are testable empirical claims, so far untested, rather than abstract ethical or philosophical positions. The dispute, therein, lies not so much in whether minors should be permitted to access predictive genetic testing but whether these empirical claims on the relative benefits or harms of testing should be assessed.

["Screening" in special situations. Assessing predictive genetic screening for hereditary breast and colorectal cancer].

PubMed

Jonas, Susanna; Wild, Claudia; Schamberger, Chantal

2003-02-01

The aim of this health technology assessment was to analyse the current scientific and genetic counselling on predictive genetic testing for hereditary breast and colorectal cancer. Predictive genetic testing will be available for several common diseases in the future and questions related to financial issues and quality standards will be raised. This report is based on a systematic/nonsystematic literature search in several databases (e.g. EmBase, Medline, Cochrane Library) and on a specific health technology assessment report (CCOHTA) and review (American Gastroenterological Ass.), respectively. Laboratory test methods, early detection methods and the benefit from prophylactic interventions were analysed and social consequences interpreted. Breast and colorectal cancer are counted among the most frequently cancer diseases. Most of them are based on random accumulation of risk factors, 5-10% show a familial determination. A hereditary modified gene is responsible for the increased cancer risk. In these families, high tumour frequency, young age at diagnosis and multiple primary tumours are remarkable. GENETIC DIAGNOSIS: Sequence analysis is the gold standard. Denaturing high performance liquid chromatography is a quick alternative method. The identification of the responsible gene defect in an affected family member is important. If the test result is positive there is an uncertainty whether the disease will develop or not, when and in which degree, which is founded in the geno-/phenotype correlation. The individual risk estimation is based upon empirical evidence. The test results affect the whole family. Currently, primary prevention is possible for familial adenomatous polyposis (celecoxib, prophylactic colectomy) and for hereditary mamma carcinoma (prophylactic mastectomy). The so-called preventive medical check-ups are early detection examinations. The evidence about early detection methods for colorectal cancer is better than for breast cancer. Prophylactic mastectomy (PM) reduces the relative breast cancer risk by approximately 90%. The question is if PM has an impact on mortality. The acceptance of PM is culture-dependent. Colectomy can be used as a prophylactic (FAP) and therapeutic method. After surgery, the cancer risk remains high and so early detection examinations are still necessary. EVIDENCE-BASED STATEMENTS: The evidence is often fragmentary and of limited quality. For objective test result presentation information about sensitivity, specificity, positive predictive value, and number needed to screen and treat, respectively, are necessary. New identification of mutations and demand will lead to an increase of predictive genetic counselling and testing. There is a gap between predictive genetic diagnosis and prediction, prevention, early detection and surgical interventions. These circumstances require a basic strategy. Since predictive genetic diagnosis is a very sensitive issue it is important to deal with it carefully in order to avoid inappropriate hopes. Thus, media, experts and politicians need to consider opportunities and limitations in their daily decision-making processes.

Genetically informed ecological niche models improve climate change predictions.

PubMed

Ikeda, Dana H; Max, Tamara L; Allan, Gerard J; Lau, Matthew K; Shuster, Stephen M; Whitham, Thomas G

2017-01-01

We examined the hypothesis that ecological niche models (ENMs) more accurately predict species distributions when they incorporate information on population genetic structure, and concomitantly, local adaptation. Local adaptation is common in species that span a range of environmental gradients (e.g., soils and climate). Moreover, common garden studies have demonstrated a covariance between neutral markers and functional traits associated with a species' ability to adapt to environmental change. We therefore predicted that genetically distinct populations would respond differently to climate change, resulting in predicted distributions with little overlap. To test whether genetic information improves our ability to predict a species' niche space, we created genetically informed ecological niche models (gENMs) using Populus fremontii (Salicaceae), a widespread tree species in which prior common garden experiments demonstrate strong evidence for local adaptation. Four major findings emerged: (i) gENMs predicted population occurrences with up to 12-fold greater accuracy than models without genetic information; (ii) tests of niche similarity revealed that three ecotypes, identified on the basis of neutral genetic markers and locally adapted populations, are associated with differences in climate; (iii) our forecasts indicate that ongoing climate change will likely shift these ecotypes further apart in geographic space, resulting in greater niche divergence; (iv) ecotypes that currently exhibit the largest geographic distribution and niche breadth appear to be buffered the most from climate change. As diverse agents of selection shape genetic variability and structure within species, we argue that gENMs will lead to more accurate predictions of species distributions under climate change. © 2016 John Wiley & Sons Ltd.

A Review of Quality of Life after Predictive Testing for and Earlier Identification of Neurodegenerative Diseases

PubMed Central

Paulsen, Jane S.; Nance, Martha; Kim, Ji-In; Carlozzi, Noelle E.; Panegyres, Peter K.; Erwin, Cheryl; Goh, Anita; McCusker, Elizabeth; Williams, Janet K.

2013-01-01

The past decade has witnessed an explosion of evidence suggesting that many neurodegenerative diseases can be detected years, if not decades, earlier than previously thought. To date, these scientific advances have not provoked any parallel translational or clinical improvements. There is an urgency to capitalize on this momentum so earlier detection of disease can be more readily translated into improved health-related quality of life for families at risk for, or suffering with, neurodegenerative diseases. In this review, we discuss health-related quality of life (HRQOL) measurement in neurodegenerative diseases and the importance of these “patient reported outcomes” for all clinical research. Next, we address HRQOL following early identification or predictive genetic testing in some neurodegenerative diseases: Huntington disease, Alzheimer's disease, Parkinson's disease, Dementia with Lewy bodies, frontotemporal dementia, amyotrophic lateral sclerosis, prion diseases, hereditary ataxias, Dentatorubral-pallidoluysian atrophy and Wilson's disease. After a brief report of available direct-to-consumer genetic tests, we address the juxtaposition of earlier disease identification with assumed reluctance towards predictive genetic testing. Forty-one studies examining health related outcomes following predictive genetic testing for neurodegenerative disease suggested that (a) extreme or catastrophic outcomes are rare; (b) consequences commonly include transiently increased anxiety and/or depression; (c) most participants report no regret; (d) many persons report extensive benefits to receiving genetic information; and (e) stigmatization and discrimination for genetic diseases are poorly understood and policy and laws are needed. Caution is appropriate for earlier identification of neurodegenerative diseases but findings suggest further progress is safe, feasible and likely to advance clinical care. PMID:24036231

The Comparative Effects of Prediction/Discussion-Based Learning Cycle, Conceptual Change Text, and Traditional Instructions on Student Understanding of Genetics

ERIC Educational Resources Information Center

Yilmaz, Diba; Tekkaya, Ceren; Sungur, Semra

2011-01-01

The present study examined the comparative effects of a prediction/discussion-based learning cycle, conceptual change text (CCT), and traditional instructions on students' understanding of genetics concepts. A quasi-experimental research design of the pre-test-post-test non-equivalent control group was adopted. The three intact classes, taught by…

Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes.

PubMed

O'Neill, Suzanne C; Rini, Christine; Goldsmith, Rachel E; Valdimarsdottir, Heiddis; Cohen, Lawrence H; Schwartz, Marc D

2009-10-01

Few data are available regarding the long-term psychological impact of uninformative BRCA1/2 test results. This study examines change in distress from pretesting to 12-months post-disclosure, with medical, family history, and psychological variables, such as pretesting perceived risk of carrying a deleterious mutation prior to testing and primary and secondary appraisals, as predictors. Two hundred and nine women with uninformative BRCA1/2 test results completed questionnaires at pretesting and 1-, 6-, and 12-month post-disclosure, including measures of anxiety and depression, cancer-specific and genetic testing distress. We used a mixed models approach to predict change in post-disclosure distress. Distress declined from pretesting to 1-month post-disclosure, but remained stable thereafter. Primary appraisals predicted all types of distress at 1-month post-disclosure. Primary and secondary appraisals predicted genetic testing distress at 1-month as well as change over time. Receiving a variant of uncertain clinical significance and entering testing with a high expectation for carrying a deleterious mutation predicted genetic testing distress that persisted through the year after testing. As a whole, women receiving uninformative BRCA1/2 test results are a resilient group. For some women, distress experienced in the month after testing does not dissipate. Variables, such as heightened pretesting perceived risk and cognitive appraisals, predict greater likelihood for sustained distress in this group and could be amenable to intervention.

Informed Choice in Direct-to-Consumer Genetic Testing for Alzheimer and Other Diseases: Lessons from Two Cases

PubMed Central

Messner, Donna A.

2011-01-01

Health-related direct-to-consumer (DTC) genetic testing has been a controversial practice. Especially problematic is predictive testing for Alzheimer disease (AD), since the disease is incurable, prevention is inconclusive, and testing does not definitively predict an individual’s future disease status. In this paper, I examine two contrasting cases of subjects who learn through genetic testing that they have an elevated risk of developing AD later in life. In these cases, the subject’s emotional response to the result is related to how well prepared she was for the real-life personal implications of possible test results. Analysis leads to the conclusion that when groups of health-related genetic tests are offered as packages by DTC companies, informed consumer choice is rendered impossible. Moreover, I argue, this marketing approach contravenes U.S. Federal Trade Commission policies for non-deceptive commercial communications. I conclude by suggesting ways to improve the prospects for informed consumer choice in DTC testing. PMID:21603253

Predictive genetic testing for neurodegenerative conditions: how should conflicting interests within families be managed?

PubMed

Stark, Zornitza; Wallace, Jane; Gillam, Lynn; Burgess, Matthew; Delatycki, Martin B

2016-10-01

Predictive genetic testing for a neurodegenerative condition in one individual in a family may have implications for other family members, in that it can reveal their genetic status. Herein a complex clinical case is explored where the testing wish of one family member was in direct conflict to that of another. The son of a person at 50% risk of an autosomal dominant neurodegenerative condition requested testing to reveal his genetic status. The main reason for the request was if he had the familial mutation, he and his partner planned to utilise preimplantation genetic diagnosis to prevent his offspring having the condition. His at-risk parent was clear that if they found out they had the mutation, they would commit suicide. We assess the potential benefits and harms from acceding to or denying such a request and present an approach to balancing competing rights of individuals within families at risk of late-onset genetic conditions, where family members have irreconcilable differences with respect to predictive testing. We argue that while it may not be possible to completely avoid harm in these situations, it is important to consider the magnitude of risks, and make every effort to limit the potential for adverse outcomes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Genetic testing in inherited polyposis syndromes - how and why?

PubMed

Lee, G H; Payne, S J; Melville, A; Clark, S K

2014-08-01

There have been recent advances in genetic testing enabling accurate diagnosis of polyposis syndromes by identifying causative gene mutations, which is essential in the management of individuals with polyposis syndrome and predictive genetic testing of their extended families. There are some similarities in clinical presentation of various polyposis syndromes, which may pose a challenge to diagnosis. In this review, we discuss the clinical presentation of the main polyposis syndromes and the process of genetic testing, including the latest advancement and future of genetic testing. We aim to reiterate the importance of genetic testing in the management of polyposis syndromes, potential pitfalls associated with genetic testing and recommendations for healthcare professionals involved with the care of polyposis patients. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Understanding of and attitudes to genetic testing for inherited retinal disease: a patient perspective.

PubMed

Willis, T A; Potrata, B; Ahmed, M; Hewison, J; Gale, R; Downey, L; McKibbin, M

2013-09-01

The views of people with inherited retinal disease are important to help develop health policy and plan services. This study aimed to record levels of understanding of and attitudes to genetic testing for inherited retinal disease, and views on the availability of testing. Telephone questionnaires comprising quantitative and qualitative items were completed with adults with inherited retinal disease. Participants were recruited via postal invitation (response rate 48%), approach at clinic or newsletters of relevant charitable organisations. Questionnaires were completed with 200 participants. Responses indicated that participants' perceived understanding of genetic testing for inherited retinal disease was variable. The majority (90%) considered testing to be good/very good and would be likely to undergo genetic testing (90%) if offered. Most supported the provision of diagnostic (97%) and predictive (92%) testing, but support was less strong for testing as part of reproductive planning. Most (87%) agreed with the statement that testing should be offered only after the individual has received genetic counselling from a professional. Subgroup analyses revealed differences associated with participant age, gender, education level and ethnicity (p<0.02). Participants reported a range of perceived benefits (eg, family planning, access to treatment) and risks (eg, impact upon family relationships, emotional consequences). Adults with inherited retinal disease strongly support the provision of publicly funded genetic testing. Support was stronger for diagnostic and predictive testing than for testing as part of reproductive planning.

Information Seeking and Intentions to Have Genetic Testing for Hereditary Cancers in Rural and Appalachian Kentuckians

ERIC Educational Resources Information Center

Kelly, Kimberly M.; Andrews, James E; Case, Donald O.; Allard, Suzanne L.; Johnson, J. David

2007-01-01

Context: Research is limited regarding the potential of genetic testing for cancer risk in rural Appalachia. Purpose: This study examined perceptions of genetic testing in a population sample of Kentuckians, with a focus on Appalachian and rural differences. The goals were to examine cultural and psychosocial factors that may predict intentions to…

Prevention for those who can pay: insurance reimbursement of genetic-based preventive interventions in the liminal state between health and disease

PubMed Central

Prince, Anya E.R.

2015-01-01

Clinical use of genetic testing to predict adult onset conditions allows individuals to minimize or circumvent disease when preventive medical interventions are available. Recent policy recommendations and changes expand patient access to information about asymptomatic genetic conditions and create mechanisms for expanded insurance coverage for genetic tests. The American College of Medical Genetics and Genomics (ACMG) recommends that laboratories provide incidental findings of medically actionable genetic variants after whole genome sequencing. The Patient Protection and Affordable Care Act (ACA) established mechanisms to mandate coverage for genetic tests, such as BRCA. The ACA and ACMG, however, do not address insurance coverage for preventive interventions. These policies equate access to testing as access to prevention, without exploring the accessibility and affordability of interventions. In reality, insurance coverage for preventive interventions in asymptomatic adults is variable given the US health insurance system's focus on treatment. Health disparities will be exacerbated if only privileged segments of society can access preventive interventions, such as prophylactic surgeries, screenings, or medication. To ensure equitable access to interventions, federal or state legislatures should mandate insurance coverage for both predictive genetic testing and recommended follow-up interventions included in a list established by an expert panel or regulatory body. PMID:26339500

Prevention for those who can pay: insurance reimbursement of genetic-based preventive interventions in the liminal state between health and disease.

PubMed

Prince, Anya E R

2015-07-01

Clinical use of genetic testing to predict adult onset conditions allows individuals to minimize or circumvent disease when preventive medical interventions are available. Recent policy recommendations and changes expand patient access to information about asymptomatic genetic conditions and create mechanisms for expanded insurance coverage for genetic tests. The American College of Medical Genetics and Genomics (ACMG) recommends that laboratories provide incidental findings of medically actionable genetic variants after whole genome sequencing. The Patient Protection and Affordable Care Act (ACA) established mechanisms to mandate coverage for genetic tests, such as BRCA. The ACA and ACMG, however, do not address insurance coverage for preventive interventions. These policies equate access to testing as access to prevention, without exploring the accessibility and affordability of interventions. In reality, insurance coverage for preventive interventions in asymptomatic adults is variable given the US health insurance system's focus on treatment. Health disparities will be exacerbated if only privileged segments of society can access preventive interventions, such as prophylactic surgeries, screenings, or medication. To ensure equitable access to interventions, federal or state legislatures should mandate insurance coverage for both predictive genetic testing and recommended follow-up interventions included in a list established by an expert panel or regulatory body.

The ethics of disclosing genetic diagnosis for Alzheimer's disease: do we need a new paradigm?

PubMed

Arribas-Ayllon, Michael

2011-01-01

Genetic testing for rare Mendelian disorders represents the dominant ethical paradigm in clinical and professional practice. Predictive testing for Huntington's disease is the model against which other kinds of genetic testing are evaluated, including testing for Alzheimer's disease. This paper retraces the historical development of ethical reasoning in relation to predictive genetic testing and reviews a range of ethical, sociological and psychological literature from the 1970s to the present. In the past, ethical reasoning has embodied a distinct style whereby normative principles are developed from a dominant disease exemplar. This reductionist approach to formulating ethical frameworks breaks down in the case of disease susceptibility. Recent developments in the genetics of Alzheimer's disease present a significant case for reconsidering the ethics of disclosing risk for common complex diseases. Disclosing the results of susceptibility testing for Alzheimer's disease has different social, psychological and behavioural consequences. Furthermore, what genetic susceptibility means to individuals and their families is diffuse and often mitigated by other factors and concerns. The ethics of disclosing a genetic diagnosis of susceptibility is contingent on whether professionals accept that probabilistic risk information is in fact 'diagnostic' and it will rely substantially on empirical evidence of how people actually perceive, recall and communicate complex risk information.

Prediction/discussion-based learning cycle versus conceptual change text: comparative effects on students' understanding of genetics

NASA Astrophysics Data System (ADS)

khawaldeh, Salem A. Al

2013-07-01

Background and purpose: The purpose of this study was to investigate the comparative effects of a prediction/discussion-based learning cycle (HPD-LC), conceptual change text (CCT) and traditional instruction on 10th grade students' understanding of genetics concepts. Sample: Participants were 112 10th basic grade male students in three classes of the same school located in an urban area. The three classes taught by the same biology teacher were randomly assigned as a prediction/discussion-based learning cycle class (n = 39), conceptual change text class (n = 37) and traditional class (n = 36). Design and method: A quasi-experimental research design of pre-test-post-test non-equivalent control group was adopted. Participants completed the Genetics Concept Test as pre-test-post-test, to examine the effects of instructional strategies on their genetics understanding. Pre-test scores and Test of Logical Thinking scores were used as covariates. Results: The analysis of covariance showed a statistically significant difference between the experimental and control groups in the favor of experimental groups after treatment. However, no statistically significant difference between the experimental groups (HPD-LC versus CCT instruction) was found. Conclusions: Overall, the findings of this study support the use of the prediction/discussion-based learning cycle and conceptual change text in both research and teaching. The findings may be useful for improving classroom practices in teaching science concepts and for the development of suitable materials promoting students' understanding of science.

Polygenic risk predicts obesity in both white and black young adults.

PubMed

Domingue, Benjamin W; Belsky, Daniel W; Harris, Kathleen Mullan; Smolen, Andrew; McQueen, Matthew B; Boardman, Jason D

2014-01-01

To test transethnic replication of a genetic risk score for obesity in white and black young adults using a national sample with longitudinal data. A prospective longitudinal study using the National Longitudinal Study of Adolescent Health Sibling Pairs (n = 1,303). Obesity phenotypes were measured from anthropometric assessments when study members were aged 18-26 and again when they were 24-32. Genetic risk scores were computed based on published genome-wide association study discoveries for obesity. Analyses tested genetic associations with body-mass index (BMI), waist-height ratio, obesity, and change in BMI over time. White and black young adults with higher genetic risk scores had higher BMI and waist-height ratio and were more likely to be obese compared to lower genetic risk age-peers. Sibling analyses revealed that the genetic risk score was predictive of BMI net of risk factors shared by siblings. In white young adults only, higher genetic risk predicted increased risk of becoming obese during the study period. In black young adults, genetic risk scores constructed using loci identified in European and African American samples had similar predictive power. Cumulative information across the human genome can be used to characterize individual level risk for obesity. Measured genetic risk accounts for only a small amount of total variation in BMI among white and black young adults. Future research is needed to identify modifiable environmental exposures that amplify or mitigate genetic risk for elevated BMI.

Effect of genetic architecture on the prediction accuracy of quantitative traits in samples of unrelated individuals.

PubMed

Morgante, Fabio; Huang, Wen; Maltecca, Christian; Mackay, Trudy F C

2018-06-01

Predicting complex phenotypes from genomic data is a fundamental aim of animal and plant breeding, where we wish to predict genetic merits of selection candidates; and of human genetics, where we wish to predict disease risk. While genomic prediction models work well with populations of related individuals and high linkage disequilibrium (LD) (e.g., livestock), comparable models perform poorly for populations of unrelated individuals and low LD (e.g., humans). We hypothesized that low prediction accuracies in the latter situation may occur when the genetics architecture of the trait departs from the infinitesimal and additive architecture assumed by most prediction models. We used simulated data for 10,000 lines based on sequence data from a population of unrelated, inbred Drosophila melanogaster lines to evaluate this hypothesis. We show that, even in very simplified scenarios meant as a stress test of the commonly used Genomic Best Linear Unbiased Predictor (G-BLUP) method, using all common variants yields low prediction accuracy regardless of the trait genetic architecture. However, prediction accuracy increases when predictions are informed by the genetic architecture inferred from mapping the top variants affecting main effects and interactions in the training data, provided there is sufficient power for mapping. When the true genetic architecture is largely or partially due to epistatic interactions, the additive model may not perform well, while models that account explicitly for interactions generally increase prediction accuracy. Our results indicate that accounting for genetic architecture can improve prediction accuracy for quantitative traits.

"Genetic exceptionalism" in medicine: clarifying the differences between genetic and nongenetic tests.

PubMed

Green, Michael J; Botkin, Jeffrey R

2003-04-01

Predictive genetic tests are now available for assessing susceptibility to a variety of conditions, including breast and colon cancer, hemochromatosis, and Alzheimer and Huntington disease. Much controversy surrounds the application of these tests, stemming from their similarities to and differences from other tests commonly used in asymptomatic persons. Some have argued that genetic tests are unique and therefore justify special consideration with regard to informed consent and privacy. This paper examines the arguments for such "genetic exceptionalism" and concludes that no clear, significant distinctions between genetic and nongenetic tests justify a different approach to testing by clinicians. Nevertheless, with many genetic tests, the results may cause stigmatization, family discord, and psychological distress. Regardless of whether a test is genetic, when this combination of characteristics is present and when health care providers are not specifically trained to interpret results, testing should be performed with particular caution and the highest standards of informed consent and privacy protection should be applied.

Genetic counseling in monogenic diabetes GCK MODY.

PubMed

Skała-Zamorowska, Eliza; Deja, Grażyna; Borowiec, Maciej; Fendler, Wojciech; Małachowska, Beata; Kamińska, Halla; Młynarski, Wojciech; Jarosz-Chobot, Przemysława

2016-01-01

Genetic testing in families with monogenic GCK MODY has predictive, diagnostic, and preventive utility. Predictive tests relate to people who have no features of the disorder themselves at the time of testing. Diagnostic tests relate to family members who have been previously diagnosed with diabetes mellitus or glucose metabolism disturbances. The preventive value of genetic testing for families is to raise awareness of the circumstances leading to glucose metabolism disorders. The detection of mutation carriers among family members of patients with GCK MODY and the determination of the clinical significance of the genetic test result. The study group included 27 families of adolescent patients with GCK MODY (39 (75%) of parents and 19 (73.08%) of siblings) monitored in the Department of Pediatrics, Endocrinology and Diabetes and in the Diabetes Clinic of John Paul II Upper Silesian Child Health Centre in Katowice in the years 2007-2012. Subjects underwent a blood sample drawing for genetic and biochemical testing. Through the genetic diagnostics we diagnosed GCK MODY in 14 (63.64%) mothers, 6 (35.29%) fathers and in 7 (36,84%) siblings. Genetic testing has contributed to the detection of 7 (26.92%) asymptomatic carriers of GCK gene mutation among parents and 3 (15,79%) asymptomatic carriers among siblings declaring no carbohydrate metabolism disturbances (before genetic testing there were no indications suggesting carbohydrate metabolism disturbances; OGTT were performed after positive genetic testing). Each case of mutation detection, which is the cause of monogenic diabetes in a patient, justifies the genetic testing in other members of his/her family. Awareness of the genetic status may allow sick family member to confirm the diagnosis, while asymptomatic mutation carriers could benefit from an early clinical observation. Consequently, in each case it gives an opportunity to take diagnostic and therapeutic measures in accordance with the current state of knowledge. © Polish Society for Pediatric Endocrinology and Diabetology.

Direct-to-consumer genetic testing: where and how does genetic counseling fit?

PubMed

Middleton, Anna; Mendes, Álvaro; Benjamin, Caroline M; Howard, Heidi Carmen

2017-05-01

Direct-to-consumer genetic testing for disease ranges from well-validated diagnostic and predictive tests to 'research' results conferring increased risks. While being targeted at public curious about their health, they are also marketed for use in reproductive decision-making or management of disease. By virtue of being 'direct-to-consumer' much of this testing bypasses traditional healthcare systems. We argue that direct-to-consumer genetic testing companies should make genetic counseling available, pre- as well as post-test. While we do not advocate that mandatory genetic counseling should gate-keep access to direct-to-consumer genetic testing, if the testing process has the potential to cause psychological distress, then companies have a responsibility to provide support and should not rely on traditional healthcare systems to pick up the pieces. A video abstract is available for this article via this link .

Consumers' views of direct-to-consumer genetic information.

PubMed

McBride, Colleen M; Wade, Christopher H; Kaphingst, Kimberly A

2010-01-01

In this report, we describe the evolution and types of genetic information provided directly to consumers, discuss potential advantages and disadvantages of these products, and review research evaluating consumer responses to direct-to-consumer (DTC) genetic testing. The available evidence to date has focused on predictive tests and does not suggest that individuals, health care providers, or health care systems have been harmed by a DTC provision of genetic information. An understanding of consumer responses to susceptibility tests has lagged behind. The Multiplex Initiative is presented as a case study of research to understand consumers' responses to DTC susceptibility tests. Three priority areas are recommended for accelerated research activities to inform public policy regarding DTC genetic information: (a) exploring consumer's long-term responses to DTC genetic testing on a comprehensive set of outcomes, (b) evaluating optimal services to support decision making about genetic testing, and (c) evaluating best practices in promoting genetic competencies among health providers.

Understanding of and attitudes to genetic testing for inherited retinal disease: a patient perspective

PubMed Central

Willis, T A; Potrata, B; Ahmed, M; Hewison, J; Gale, R; Downey, L; McKibbin, M

2013-01-01

Background/aims The views of people with inherited retinal disease are important to help develop health policy and plan services. This study aimed to record levels of understanding of and attitudes to genetic testing for inherited retinal disease, and views on the availability of testing. Methods Telephone questionnaires comprising quantitative and qualitative items were completed with adults with inherited retinal disease. Participants were recruited via postal invitation (response rate 48%), approach at clinic or newsletters of relevant charitable organisations. Results Questionnaires were completed with 200 participants. Responses indicated that participants’ perceived understanding of genetic testing for inherited retinal disease was variable. The majority (90%) considered testing to be good/very good and would be likely to undergo genetic testing (90%) if offered. Most supported the provision of diagnostic (97%) and predictive (92%) testing, but support was less strong for testing as part of reproductive planning. Most (87%) agreed with the statement that testing should be offered only after the individual has received genetic counselling from a professional. Subgroup analyses revealed differences associated with participant age, gender, education level and ethnicity (p<0.02). Participants reported a range of perceived benefits (eg, family planning, access to treatment) and risks (eg, impact upon family relationships, emotional consequences). Conclusions Adults with inherited retinal disease strongly support the provision of publicly funded genetic testing. Support was stronger for diagnostic and predictive testing than for testing as part of reproductive planning. PMID:23813418

The social dynamics of genetic testing: the case of Fragile-X.

PubMed

Nelkin, D

1996-12-01

This article considers a program to screen school children for Fragile-X Syndrome as a way to explore several features of the growing practice of genetic testing in American society. These include the common practice of predictive testing in nonclinical settings; the economic, entrepreneurial, and policy interests that are driving the development of genetic screening programs; and the public support for genetic testing even when there are no effective therapeutic interventions. Drawing from research on popular images of genetics, I argue that cultural beliefs and expectations, widely conveyed through popular narratives, are encouraging the search for diagnostic information and enhancing the appeal of genetic explanations for a growing range of conditions.

Disparities in genetic testing: thinking outside the BRCA box.

PubMed

Hall, Michael J; Olopade, Olufunmilayo I

2006-05-10

The impact of predictive genetic testing on cancer care can be measured by the increased demand for and utilization of genetic services as well as in the progress made in reducing cancer risks in known mutation carriers. Nonetheless, differential access to and utilization of genetic counseling and cancer predisposition testing among underserved racial and ethnic minorities compared with the white population has led to growing health care disparities in clinical cancer genetics that are only beginning to be addressed. Furthermore, deficiencies in the utility of genetic testing in underserved populations as a result of limited testing experience and in the effectiveness of risk-reducing interventions compound access and knowledge-base disparities. The recent literature on racial/ethnic health care disparities is briefly reviewed, and is followed by a discussion of the current limitations of risk assessment and genetic testing outside of white populations. The importance of expanded testing in underserved populations is emphasized.

Psychological opportunities and hazards in predictive genetic testing for cancer risk.

PubMed

Codori, A M

1997-03-01

Although the availability of genetic tests seems like an unequivocally favorable turn of events, they are, in fact, not without controversy. At the center of the controversy is a question regarding the risks and benefits of genetic testing. Many geneticists, ethicists, psychologists, and persons at risk for cancer are concerned about the potentially adverse psychological effects of genetic testing on tested persons and their families. In addition, the screening and interventions that are useful in the general population remain to be shown effective in those with high genetic cancer risk. Consequently, there have been calls for caution in moving genetic testing out of research laboratories and into commercial laboratories until their impact and the effectiveness of cancer prevention strategies can be studied. This article examines the arguments and data for and against this caution, citing examples related to hereditary nonpolyposis colon cancer and drawing upon literature on testing for other genetic diseases.

A test of the hypothesis that correlational selection generates genetic correlations.

PubMed

Roff, Derek A; Fairbairn, Daphne J

2012-09-01

Theory predicts that correlational selection on two traits will cause the major axis of the bivariate G matrix to orient itself in the same direction as the correlational selection gradient. Two testable predictions follow from this: for a given pair of traits, (1) the sign of correlational selection gradient should be the same as that of the genetic correlation, and (2) the correlational selection gradient should be positively correlated with the value of the genetic correlation. We test this hypothesis with a meta-analysis utilizing empirical estimates of correlational selection gradients and measures of the correlation between the two focal traits. Our results are consistent with both predictions and hence support the underlying hypothesis that correlational selection generates a genetic correlation between the two traits and hence orients the bivariate G matrix. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

The Causal Meaning of Genomic Predictors and How It Affects Construction and Comparison of Genome-Enabled Selection Models

PubMed Central

Valente, Bruno D.; Morota, Gota; Peñagaricano, Francisco; Gianola, Daniel; Weigel, Kent; Rosa, Guilherme J. M.

2015-01-01

The term “effect” in additive genetic effect suggests a causal meaning. However, inferences of such quantities for selection purposes are typically viewed and conducted as a prediction task. Predictive ability as tested by cross-validation is currently the most acceptable criterion for comparing models and evaluating new methodologies. Nevertheless, it does not directly indicate if predictors reflect causal effects. Such evaluations would require causal inference methods that are not typical in genomic prediction for selection. This suggests that the usual approach to infer genetic effects contradicts the label of the quantity inferred. Here we investigate if genomic predictors for selection should be treated as standard predictors or if they must reflect a causal effect to be useful, requiring causal inference methods. Conducting the analysis as a prediction or as a causal inference task affects, for example, how covariates of the regression model are chosen, which may heavily affect the magnitude of genomic predictors and therefore selection decisions. We demonstrate that selection requires learning causal genetic effects. However, genomic predictors from some models might capture noncausal signal, providing good predictive ability but poorly representing true genetic effects. Simulated examples are used to show that aiming for predictive ability may lead to poor modeling decisions, while causal inference approaches may guide the construction of regression models that better infer the target genetic effect even when they underperform in cross-validation tests. In conclusion, genomic selection models should be constructed to aim primarily for identifiability of causal genetic effects, not for predictive ability. PMID:25908318

[Analytic methods for seed models with genotype x environment interactions].

PubMed

Zhu, J

1996-01-01

Genetic models with genotype effect (G) and genotype x environment interaction effect (GE) are proposed for analyzing generation means of seed quantitative traits in crops. The total genetic effect (G) is partitioned into seed direct genetic effect (G0), cytoplasm genetic of effect (C), and maternal plant genetic effect (Gm). Seed direct genetic effect (G0) can be further partitioned into direct additive (A) and direct dominance (D) genetic components. Maternal genetic effect (Gm) can also be partitioned into maternal additive (Am) and maternal dominance (Dm) genetic components. The total genotype x environment interaction effect (GE) can also be partitioned into direct genetic by environment interaction effect (G0E), cytoplasm genetic by environment interaction effect (CE), and maternal genetic by environment interaction effect (GmE). G0E can be partitioned into direct additive by environment interaction (AE) and direct dominance by environment interaction (DE) genetic components. GmE can also be partitioned into maternal additive by environment interaction (AmE) and maternal dominance by environment interaction (DmE) genetic components. Partitions of genetic components are listed for parent, F1, F2 and backcrosses. A set of parents, their reciprocal F1 and F2 seeds is applicable for efficient analysis of seed quantitative traits. MINQUE(0/1) method can be used for estimating variance and covariance components. Unbiased estimation for covariance components between two traits can also be obtained by the MINQUE(0/1) method. Random genetic effects in seed models are predictable by the Adjusted Unbiased Prediction (AUP) approach with MINQUE(0/1) method. The jackknife procedure is suggested for estimation of sampling variances of estimated variance and covariance components and of predicted genetic effects, which can be further used in a t-test for parameter. Unbiasedness and efficiency for estimating variance components and predicting genetic effects are tested by Monte Carlo simulations.

Psychological Factors Associated with Genetic Test Decision-Making among Parents of Children with Autism Spectrum Disorders in Taiwan

ERIC Educational Resources Information Center

Xu, Lei; Richman, Alice R.

2015-01-01

Making decisions to undergo Autism Spectrum Disorders (ASD) genetic testing can be challenging. It is important to understand how the perceptions of affected individuals might influence testing decision-making. Although evidence has shown that psychological factors are important in predicting testing decisions, affect-type variables have been…

Genetic testing in asymptomatic minors Background considerations towards ESHG Recommendations

PubMed Central

Borry, Pascal; Evers-Kiebooms, Gerry; Cornel, Martina C; Clarke, Angus; Dierickx, Kris

2009-01-01

Although various guidelines and position papers have discussed, in the past, the ethical aspects of genetic testing in asymptomatic minors, the European Society of Human Genetics had not earlier endorsed any set of guidelines exclusively focused on this issue. This paper has served as a background document in preparation of the development of the policy recommendations of the Public and Professional Committee of the European Society of Human Genetics. This background paper first discusses some general considerations with regard to the provision of genetic tests to minors. It discusses the concept of best interests, participation of minors in health-care decisions, parents' responsibilities to share genetic information, the role of clinical genetics and the health-care system in communication within the family. Second, it discusses, respectively, the presymptomatic and predictive genetic testing for adult-onset disorders, childhood-onset disorders and carrier testing. PMID:19277061

Linking extinction-colonization dynamics to genetic structure in a salamander metapopulation.

PubMed

Cosentino, Bradley J; Phillips, Christopher A; Schooley, Robert L; Lowe, Winsor H; Douglas, Marlis R

2012-04-22

Theory predicts that founder effects have a primary role in determining metapopulation genetic structure. However, ecological factors that affect extinction-colonization dynamics may also create spatial variation in the strength of genetic drift and migration. We tested the hypothesis that ecological factors underlying extinction-colonization dynamics influenced the genetic structure of a tiger salamander (Ambystoma tigrinum) metapopulation. We used empirical data on metapopulation dynamics to make a priori predictions about the effects of population age and ecological factors on genetic diversity and divergence among 41 populations. Metapopulation dynamics of A. tigrinum depended on wetland area, connectivity and presence of predatory fish. We found that newly colonized populations were more genetically differentiated than established populations, suggesting that founder effects influenced genetic structure. However, ecological drivers of metapopulation dynamics were more important than age in predicting genetic structure. Consistent with demographic predictions from metapopulation theory, genetic diversity and divergence depended on wetland area and connectivity. Divergence was greatest in small, isolated wetlands where genetic diversity was low. Our results show that ecological factors underlying metapopulation dynamics can be key determinants of spatial genetic structure, and that habitat area and isolation may mediate the contributions of drift and migration to divergence and evolution in local populations.

Ethics and Neuropsychiatric Genetics: A Review of Major Issues

PubMed Central

Hoge, Steven K.; Appelbaum, Paul S.

2012-01-01

Advances in neuropsychiatric genetics hold great hopes for improved prevention, diagnosis, and treatment. However, the power of genetic testing to identify individuals at increased risk for disorders and to convey information about relatives creates a set of complex ethical issues. Public attitudes are inevitably affected by the shadow of eugenics, with its history of distorting scientific findings to serve socio-political ends. Nonetheless, the growing availability of genetic tests means that more patients will seek genetic information, and physicians must manage the process of informed consent to allow meaningful decisions. Patients should be helped to understand the often-limited predictive power of current knowledge, potential psychological impact, risks of stigma and discrimination, and possible implications for family members. Decisions for predictive testing of children raise additional concerns, including distortions of family dynamics and negative effects on children’s self-image; testing is best deferred until adulthood unless preventive interventions exist. Pharmacogenomic testing, part of personalized medicine, may bring collateral susceptibility information for which patients should be prepared. The implications of genetic findings for families raise the question of whether physicians have duties to inform family members of implications for their health. Finally, participation in research in neuropsychiatric genetics evokes a broad range of ethical concerns, including the contentious issue of the extent to which results should be returned to individual subjects. As genetic science becomes more widely applied, the public will become more sophisticated and will be likely to demand a greater role in determining social policy on these issues. PMID:22272758

Commerce and genetic diagnostics.

PubMed

Silverman, Paul H

1995-01-01

The revolution in molecular biology and molecular genetics has begun to reveal the sequence of events that links genes and disease. As a result of activities such as the Human Genome Project, a parallel revolution in technology is bringing nearer to hand the possibility of readily available genetic diagnostics. Genetic testing services have begun to move out of the academic medical centers and into the private enterprise arena. Under these circumstances it is important to understand the factors affecting the availability and application of this powerful predictive tool in a for-profit mode. How does the marketplace encourage or discourage genetic testing? Will the same market influences that generate pharmaceutical sales be operating to "sell" genetic tests?

Integrating paleoecology and genetics of bird populations in two sky island archipelagos.

PubMed

McCormack, John E; Bowen, Bonnie S; Smith, Thomas B

2008-06-27

Genetic tests of paleoecological hypotheses have been rare, partly because recent genetic divergence is difficult to detect and time. According to fossil plant data, continuous woodland in the southwestern USA and northern Mexico became fragmented during the last 10,000 years, as warming caused cool-adapted species to retreat to high elevations. Most genetic studies of resulting 'sky islands' have either failed to detect recent divergence or have found discordant evidence for ancient divergence. We test this paleoecological hypothesis for the region with intraspecific mitochondrial DNA and microsatellite data from sky-island populations of a sedentary bird, the Mexican jay (Aphelocoma ultramarina). We predicted that populations on different sky islands would share common, ancestral alleles that existed during the last glaciation, but that populations on each sky island, owing to their isolation, would contain unique variants of postglacial origin. We also predicted that divergence times estimated from corrected genetic distance and a coalescence model would post-date the last glacial maximum. Our results provide multiple independent lines of support for postglacial divergence, with the predicted pattern of shared and unique mitochondrial DNA haplotypes appearing in two independent sky-island archipelagos, and most estimates of divergence time based on corrected genetic distance post-dating the last glacial maximum. Likewise, an isolation model based on multilocus gene coalescence indicated postglacial divergence of five pairs of sky islands. In contrast to their similar recent histories, the two archipelagos had dissimilar historical patterns in that sky islands in Arizona showed evidence for older divergence, suggesting different responses to the last glaciation. This study is one of the first to provide explicit support from genetic data for a postglacial divergence scenario predicted by one of the best paleoecological records in the world. Our results demonstrate that sky islands act as generators of genetic diversity at both recent and historical timescales and underscore the importance of thorough sampling and the use of loci with fast mutation rates to studies that test hypotheses concerning recent genetic divergence.

Development of a forensic skin colour predictive test.

PubMed

Maroñas, Olalla; Phillips, Chris; Söchtig, Jens; Gomez-Tato, Antonio; Cruz, Raquel; Alvarez-Dios, José; de Cal, María Casares; Ruiz, Yarimar; Fondevila, Manuel; Carracedo, Ángel; Lareu, María V

2014-11-01

There is growing interest in skin colour prediction in the forensic field. However, a lack of consensus approaches for recording skin colour phenotype plus the complicating factors of epistatic effects, environmental influences such as exposure to the sun and unidentified genetic variants, present difficulties for the development of a forensic skin colour predictive test centred on the most strongly associated SNPs. Previous studies have analysed skin colour variation in single unadmixed population groups, including South Asians (Stokowski et al., 2007, Am. J. Hum. Genet, 81: 1119-32) and Europeans (Jacobs et al., 2013, Hum Genet. 132: 147-58). Nevertheless, a major challenge lies in the analysis of skin colour in admixed individuals, where co-ancestry proportions do not necessarily dictate any one person's skin colour. Our study sought to analyse genetic differences between African, European and admixed African-European subjects where direct spectrometric measurements and photographs of skin colour were made in parallel. We identified strong associations to skin colour variation in the subjects studied from a pigmentation SNP discovery panel of 59 markers and developed a forensic online classifier based on naïve Bayes analysis of the SNP profiles made. A skin colour predictive test is described using the ten most strongly associated SNPs in 8 genes linked to skin pigmentation variation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Are the kids really all right? Direct-to-consumer genetic testing in children: are company policies clashing with professional norms?

PubMed

Howard, Heidi Carmen; Avard, Denise; Borry, Pascal

2011-11-01

The genetic testing of minors within the direct-to-consumer (DTC) genetic testing (GT) context has been given relatively little attention. The issue of testing healthy children for diseases that would only develop in adulthood raises many important ethical, legal and social issues. As genetic testing is now available outside of the traditional health care system, often without even the intermediate of a health care professional, we surveyed 37 DTC GT companies regarding their policies for testing in children. Although the response rate is relatively low (35%, 13/37), our findings reveal that a clear majority of companies do perform genetic testing in minors. As such, companies testing for adult onset diseases are acting in contradiction of established professional guidelines, which state, among others, that, for predictive genetic testing, the availability of therapeutic or preventive measures is necessary for testing to be performed in asymptomatic minors. The community of stakeholders in children's health care and genetic testing should, therefore, decide which standards need to be upheld by DTC GT companies and ensure that these are met.

Direct-to-consumer genetic testing: good, bad or benign?

PubMed

Caulfield, T; Ries, N M; Ray, P N; Shuman, C; Wilson, B

2010-02-01

A wide variety of genetic tests are now being marketed and sold in direct-to-consumer (DTC) commercial transactions. However, risk information revealed through many DTC testing services, especially those based on emerging genome wide-association studies, has limited predictive value for consumers. Some commentators contend that tests are being marketed prematurely, while others support rapid translation of genetic research findings to the marketplace. The potential harms and benefits of DTC access to genetic testing are not yet well understood, but some large-scale studies have recently been launched to examine how consumers understand and use genetic risk information. Greater consumer access to genetic tests creates a need for continuing education for health care professionals so they can respond to patients' inquiries about the benefits, risks and limitations of DTC services. Governmental bodies in many jurisdictions are considering options for regulating practices of DTC genetic testing companies, particularly to govern quality of commercial genetic tests and ensure fair and truthful advertising. Intersectoral initiatives involving government regulators, professional bodies and industry are important to facilitate development of standards to govern this rapidly developing area of personalized genomic commerce.

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

PubMed

Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

2014-03-01

The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case-control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD.

Genetic and linguistic coevolution in Northern Island Melanesia.

PubMed

Hunley, Keith; Dunn, Michael; Lindström, Eva; Reesink, Ger; Terrill, Angela; Healy, Meghan E; Koki, George; Friedlaender, Françoise R; Friedlaender, Jonathan S

2008-10-01

Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions.

Genetic and Linguistic Coevolution in Northern Island Melanesia

PubMed Central

Hunley, Keith; Dunn, Michael; Lindström, Eva; Reesink, Ger; Terrill, Angela; Healy, Meghan E.; Koki, George; Friedlaender, Françoise R.; Friedlaender, Jonathan S.

2008-01-01

Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions. PMID:18974871

Recent advances in the development and use of molecular tests to predict antimicrobial resistance in Neisseria gonorrhoeae.

PubMed

Donà, Valentina; Low, Nicola; Golparian, Daniel; Unemo, Magnus

2017-09-01

The number of genetic tests, mostly real-time PCRs, to detect antimicrobial resistance (AMR) determinants and predict AMR in Neisseria gonorrhoeae is increasing. Several of these assays are promising, but there are important shortcomings and few assays have been adequately validated and quality assured. Areas covered: Recent advances, focusing on publications since 2012, in the development and use of molecular tests to predict gonococcal AMR for surveillance and for clinical use, advantages and disadvantages of these tests and of molecular AMR prediction compared with phenotypic AMR testing, and future perspectives for effective use of molecular AMR tests for different purposes. Expert commentary: Several challenges for direct testing of clinical, especially extra-genital, specimens remain. The choice of molecular assay needs to consider the assay target, quality controls, sample types, limitations intrinsic to molecular technologies, and specific to the chosen methodology, and the intended use of the test. Improved molecular- and particularly genome-sequencing-based methods will supplement AMR testing for surveillance purposes, and translate into point-of-care tests that will lead to personalized treatments, while sparing the last available empiric treatment option (ceftriaxone). However, genetic AMR prediction will never completely replace phenotypic AMR testing, which detects also AMR due to unknown AMR determinants.

Sex-specific genetic variance and the evolution of sexual dimorphism: a systematic review of cross-sex genetic correlations.

PubMed

Poissant, Jocelyn; Wilson, Alastair J; Coltman, David W

2010-01-01

The independent evolution of the sexes may often be constrained if male and female homologous traits share a similar genetic architecture. Thus, cross-sex genetic covariance is assumed to play a key role in the evolution of sexual dimorphism (SD) with consequent impacts on sexual selection, population dynamics, and speciation processes. We compiled cross-sex genetic correlations (r(MF)) estimates from 114 sources to assess the extent to which the evolution of SD is typically constrained and test several specific hypotheses. First, we tested if r(MF) differed among trait types and especially between fitness components and other traits. We also tested the theoretical prediction of a negative relationship between r(MF) and SD based on the expectation that increases in SD should be facilitated by sex-specific genetic variance. We show that r(MF) is usually large and positive but that it is typically smaller for fitness components. This demonstrates that the evolution of SD is typically genetically constrained and that sex-specific selection coefficients may often be opposite in sign due to sub-optimal levels of SD. Most importantly, we confirm that sex-specific genetic variance is an important contributor to the evolution of SD by validating the prediction of a negative correlation between r(MF) and SD.

Patient compliance based on genetic medicine: a literature review.

PubMed

Schneider, Kai Insa; Schmidtke, Jörg

2014-01-01

For this literature review, medical literature data bases were searched for studies on patient compliance after genetic risk assessment. The review focused on conditions where secondary or tertiary preventive options exist, namely cancer syndromes (BRCA-related cancer, HNPCC/colon cancer), hemochromatosis, thrombophilia, smoking cessation, and obesity. As a counterpart, patient compliance was assessed regarding medication adherence and medical advice in some of the most epidemiologically important conditions (including high blood pressure, metabolic syndrome, and coronary heart disease) after receiving medical advice based on nongenetic risk information or a combination of genetic and nongenetic risk information. In the majority of studies based on genetic risk assessments, patients were confronted with predictive rather than diagnostic genetic profiles. Most of the studies started from a knowledge base around 10 years ago when DNA testing was at an early stage, limited in scope and specificity, and costly. The major result is that overall compliance of patients after receiving a high-risk estimate from genetic testing for a given condition is high. However, significant behavior change does not take place just because the analyte is "genetic." Many more factors play a role in the complex process of behavioral tuning. Without adequate counseling and guidance, patients may interpret risk estimates of predictive genetic testing with an increase in fear and anxiety.

Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

PubMed Central

Hayden, Michael

1988-01-01

Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

The likely financial effects on individuals, industry and commerce of the use of genetic information.

PubMed Central

Ross, T

1997-01-01

In this paper I look at the financial implications of genetic testing, particularly in the employment and pensions fields. I have generally not covered life insurance, as that is covered in other papers in this Discussion Meeting. However, the issues are similar, although the emphasis is different. Inevitably there is an element of speculation involved; genetic testing is in its infancy and so we cannot predict either what information we will be able to obtain through genetic testing, nor the uses that may be devised for this information. PMID:9304677

Support Seeking or Familial Obligation: An Investigation of Motives for Disclosing Genetic Test Results.

PubMed

Greenberg, Marisa; Smith, Rachel A

2016-01-01

Genetic test results reveal not only personal information about a person's likelihood of certain medical conditions but also information about the person's genetic relatives. Given the familial nature of genetic information, one's obligation to protect family members may be a motive for disclosing genetic test results, but this claim has not been methodically tested. Existing models of disclosure decision making presume self-interested motives, such as seeking social support, instead of other-interested motives, like familial obligation. This study investigated young adults' (N = 173) motives to share a genetic-based health condition, alpha-1 antitrypsin deficiency, after reading a hypothetical vignette. Results show that social support and familial obligation were both reported as motives for disclosure. In fact, some participants reported familial obligation as their primary motivator for disclosure. Finally, stronger familial obligation predicted increased likelihood of disclosing hypothetical genetic test results. Implications of these results were discussed in reference to theories of disclosure decision-making models and the practice of genetic disclosures.

Simulation, prediction, and genetic analyses of daily methane emissions in dairy cattle.

PubMed

Yin, T; Pinent, T; Brügemann, K; Simianer, H; König, S

2015-08-01

This study presents an approach combining phenotypes from novel traits, deterministic equations from cattle nutrition, and stochastic simulation techniques from animal breeding to generate test-day methane emissions (MEm) of dairy cows. Data included test-day production traits (milk yield, fat percentage, protein percentage, milk urea nitrogen), conformation traits (wither height, hip width, body condition score), female fertility traits (days open, calving interval, stillbirth), and health traits (clinical mastitis) from 961 first lactation Brown Swiss cows kept on 41 low-input farms in Switzerland. Test-day MEm were predicted based on the traits from the current data set and 2 deterministic prediction equations, resulting in the traits labeled MEm1 and MEm2. Stochastic simulations were used to assign individual concentrate intake in dependency of farm-type specifications (requirement when calculating MEm2). Genetic parameters for MEm1 and MEm2 were estimated using random regression models. Predicted MEm had moderate heritabilities over lactation and ranged from 0.15 to 0.37, with highest heritabilities around DIM 100. Genetic correlations between MEm1 and MEm2 ranged between 0.91 and 0.94. Antagonistic genetic correlations in the range from 0.70 to 0.92 were found for the associations between MEm2 and milk yield. Genetic correlations between MEm with days open and with calving interval increased from 0.10 at the beginning to 0.90 at the end of lactation. Genetic relationships between MEm2 and stillbirth were negative (0 to -0.24) from the beginning to the peak phase of lactation. Positive genetic relationships in the range from 0.02 to 0.49 were found between MEm2 with clinical mastitis. Interpretation of genetic (co)variance components should also consider the limitations when using data generated by prediction equations. Prediction functions only describe that part of MEm which is dependent on the factors and effects included in the function. With high probability, there are more important effects contributing to variations of MEm that are not explained or are independent from these functions. Furthermore, autocorrelations exist between indicator traits and predicted MEm. Nevertheless, this integrative approach, combining information from dairy cattle nutrition with dairy cattle genetics, generated novel traits which are difficult to record on a large scale. The simulated data basis for MEm was used to determine the size of a cow calibration group for genomic selection. A calibration group including 2,581 cows with MEm phenotypes was competitive with conventional breeding strategies. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: a cross-sectional survey.

PubMed

Hann, Katie E J; Fraser, Lindsay; Side, Lucy; Gessler, Sue; Waller, Jo; Sanderson, Saskia C; Freeman, Madeleine; Jacobs, Ian; Lanceley, Anne

2017-12-16

Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals' (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one's own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and 'others'. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population-based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process.

Hopes and Expectations Regarding Genetic Testing for Schizophrenia Among Young Adults at Clinical High-Risk for Psychosis.

PubMed

Friesen, Phoebe; Lawrence, Ryan E; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

2016-11-01

Genetic tests for schizophrenia could introduce both risks and benefits. Little is known about the hopes and expectations of young adults at clinical high-risk for psychosis concerning genetic testing for schizophrenia, despite the fact that these youth could be among those highly affected by such tests. We conducted semistructured interviews with 15 young adults at clinical high-risk for psychosis to ask about their interest, expectations, and hopes regarding genetic testing for schizophrenia. Most participants reported a high level of interest in genetic testing for schizophrenia, and the majority said they would take such a test immediately if it were available. Some expressed far-reaching expectations for a genetic test, such as predicting symptom severity and the timing of symptom onset. Several assumed that genetic testing would be accompanied by interventions to prevent schizophrenia. Participants anticipated mixed reactions on finding out they had a genetic risk for schizophrenia, suggesting that they might feel both a sense of relief and a sense of hopelessness. We suggest that genetic counseling could play an important role in counteracting a culture of genetic over-optimism and helping young adults at clinical high-risk for psychosis understand the limitations of genetic testing. Counseling sessions could also invite individuals to explore how receiving genetic risk information might impact their well-being, as early evidence suggests that some psychological factors help individuals cope, whereas others heighten distress related to genetic test results.

Exploring the Potential of Direct-To-Consumer Genomic Test Data for Predicting Adverse Drug Events.

PubMed

Zhang, Patrick M; Sarkar, Indra Neil

2018-01-01

Recent technological advancements in genetic testing and the growing accessibility of public genomic data provide researchers with a unique avenue to approach personalized medicine. This feasibility study examined the potential of direct-to-consumer (DTC) genomic tests (focusing on 23andMe) in research and clinical applications. In particular, we combined population genetics information from the Personal Genome Project with adverse event reports from AEOLUS and pharmacogenetic information from PharmGKB. Primarily, associations between drugs based on co-occurring genetic variations and associations between variants and adverse events were used to assess the potential for leveraging single nucleotide polymorphism information from 23andMe. The results of this study suggest potential clinical uses of DTC tests in light of potential drug interactions. Furthermore, the results suggest great potential for analyzing associations at a population level to facilitate knowledge discovery in the realm of predicting adverse drug events.

Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy.

PubMed

de Haas, Sanne; Delmar, Paul; Bansal, Aruna T; Moisse, Matthieu; Miles, David W; Leighl, Natasha; Escudier, Bernard; Van Cutsem, Eric; Carmeliet, Peter; Scherer, Stefan J; Pallaud, Celine; Lambrechts, Diether

2014-10-01

Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.

Genetic and phylogenetic consequences of island biogeography.

PubMed

Johnson, K P; Adler, F R; Cherry, J L

2000-04-01

Island biogeography theory predicts that the number of species on an island should increase with island size and decrease with island distance to the mainland. These predictions are generally well supported in comparative and experimental studies. These ecological, equilibrium predictions arise as a result of colonization and extinction processes. Because colonization and extinction are also important processes in evolution, we develop methods to test evolutionary predictions of island biogeography. We derive a population genetic model of island biogeography that incorporates island colonization, migration of individuals from the mainland, and extinction of island populations. The model provides a means of estimating the rates of migration and extinction from population genetic data. This model predicts that within an island population the distribution of genetic divergences with respect to the mainland source population should be bimodal, with much of the divergence dating to the colonization event. Across islands, this model predicts that populations on large islands should be on average more genetically divergent from mainland source populations than those on small islands. Likewise, populations on distant islands should be more divergent than those on close islands. Published observations of a larger proportion of endemic species on large and distant islands support these predictions.

What should we want to know about our future? A Kantian view on predictive genetic testing.

PubMed

Heinrichs, Bert

2005-01-01

Recent advances in genomic research have led to the development of new diagnostic tools, including tests which make it possible to predict the future occurrence of monogenetic diseases (e.g. Chorea Huntington) or to determine increased susceptibilities to the future development of more complex diseases (e.g. breast cancer). The use of such tests raises a number of ethical, legal and social issues which are usually discussed in terms of rights. However, in the context of predictive genetic tests a key question arises which lies beyond the concept of rights, namely, What should we want to know about our future? In the following I shall discuss this question against the background of Kant's Doctrine of Virtue. It will be demonstrated that the system of duties of virtue that Kant elaborates in the second part of his Metaphysics of Morals offers a theoretical framework for addressing the question of a proper scope of future knowledge as provided by genetic tests. This approach can serve as a source of moral guidance complementary to a justice perspective. It does, however, not rest on the-rather problematic--claim to be able to define what the "good life" is.

Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes

PubMed Central

2010-01-01

Many private companies offer direct-to-consumer (DTC) genetic testing services. Some tests may detect severe and highly penetrant monogenic disorders, while other tests are for genetic variants found associated with increased susceptibility for common and complex diseases in large-scale population studies. Through its Public and Professional Policy committee followed by member and expert consultation, the European Society of Human Genetics has developed the following policy on advertising and provision of predictive genetic tests by such DTC companies: (1) clinical utility of a genetic test shall be an essential criterion for deciding to offer this test to a person or a group of persons; (2) laboratories providing genetic tests should comply with accepted quality standards, including those regarding laboratory personnel qualifications; (3) information about the purpose and appropriateness of testing should be given before the test is done; (4) genetic counselling appropriate to the type of test and disease should be offered; and for some tests psychosocial evaluation and follow-up should be available; (5) privacy and confidentiality of sensitive genetic information should be secured and the data safely guarded; (6) special measures should be taken to avoid inappropriate testing of minors and other legally incapacitated persons; (7) all claims regarding genetic tests should be transparent; advertisement should be unbiased and marketing of genetic tests should be fair; (8) in biomedical research, health care and marketing, respect should be given to relevant ethical principles, as well as international treaties and recommendations regarding genetic testing; and (9) nationally approved guidelines considering all the above-mentioned aspects should be made and followed. PMID:20736974

Investigating Married Adults' Communal Coping with Genetic Health Risk and Perceived Discrimination

PubMed Central

Smith, Rachel A.; Sillars, Alan; Chesnut, Ryan P.; Zhu, Xun

2017-01-01

Increased genetic testing in personalized medicine presents unique challenges for couples, including managing disease risk and potential discrimination as a couple. This study investigated couples' conflicts and support gaps as they coped with perceived genetic discrimination. We also explored the degree to which communal coping was beneficial in reducing support gaps, and ultimately stress. Dyadic analysis of married adults (N = 266, 133 couples), in which one person had the genetic risk for serious illness, showed that perceived discrimination predicted more frequent conflicts about AATD-related treatment, privacy boundaries, and finances, which, in turn, predicted wider gaps in emotion and esteem support, and greater stress for both spouses. Communal coping predicted lower support gaps for both partners and marginally lower stress. PMID:29731540

Investigating Married Adults' Communal Coping with Genetic Health Risk and Perceived Discrimination.

PubMed

Smith, Rachel A; Sillars, Alan; Chesnut, Ryan P; Zhu, Xun

2018-01-01

Increased genetic testing in personalized medicine presents unique challenges for couples, including managing disease risk and potential discrimination as a couple. This study investigated couples' conflicts and support gaps as they coped with perceived genetic discrimination. We also explored the degree to which communal coping was beneficial in reducing support gaps, and ultimately stress. Dyadic analysis of married adults ( N = 266, 133 couples), in which one person had the genetic risk for serious illness, showed that perceived discrimination predicted more frequent conflicts about AATD-related treatment, privacy boundaries, and finances, which, in turn, predicted wider gaps in emotion and esteem support, and greater stress for both spouses. Communal coping predicted lower support gaps for both partners and marginally lower stress.

Genetic Testing and Neuroimaging: Trading off Benefit and Risk for Youth with Mental Illness

PubMed Central

Lee, Grace; Mizgalewicz, Ania; Borgelt, Emily; Illes, Judy

2015-01-01

According to the World Health Organization, mental illness is one of the leading causes of disability worldwide. The first onset of mental illness usually occurs during childhood or adolescence. Neuroimaging and genetic testing have been invaluable in research on behavioral and intentional disorders, particularly with their potential to lead to improved diagnostic and predictive capabilities and to decrease the associated burdens of disease. The present study focused specifically the perspectives of mental health providers on the role of neuroimaging and genetic testing in clinical practice with children and adolescents. We interviewed 38 psychiatrists, psychologists, and allied mental health professionals who work primarily with youth about their receptivity towards either the use of neuroimaging or genetic testing. Interviews probed the role they foresee for these modalities for prediction, diagnosis, and treatment planning, and the benefits and risks they anticipate. Practitioners anticipated three major benefits associated with clinical introduction of imaging and genetic testing in the mental health care for youth: (1) improved understanding of illness, (2) more accurate diagnosis than available through conventional clinical examination, and (3) validation of treatment plans. They also perceived three major risks: (1) potential adverse impacts on employment and insurance as adolescents reach adulthood, (2) misuse or misinterpretation of the imaging or genetic data, and (3) infringements on self-esteem or self-motivation. Movement of brain imaging and genetic testing into clinical care will require a delicate balance of biology and respect for autonomy in the still-evolving cognitive and affective world of young individuals. PMID:26949737

77 FR 33748 - International Conference on Harmonisation; Guidance on S2(R1) Genotoxicity Testing and Data...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-07

... standard genetic toxicology battery for prediction of potential human risks, and on interpreting results... followup testing and interpretation of positive results in vitro and in vivo in the standard genetic... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2008-D-0178...

Genetic Testing for Minors: Comparison between Italian and British Guidelines

PubMed Central

Tozzo, Pamela; Caenazzo, Luciana; Rodriguez, Daniele

2012-01-01

Genetic testing in children raises many important ethical, legal, and social issues. One of the main concerns is the ethically inappropriate genetic testing of minors. Various European countries established professional guidelines which reflect the different countries perspectives regarding the main ethical issues involved. In this paper, we analyze the Italian and the British guidelines by highlighting differences and similarities. We discuss presymptomatic, predictive, and carrier testing because we consider them to be the more ethically problematic types of genetic testing in minors. In our opinion, national guidelines should take into account the different needs in clinical practice. At the same time, in the case of genetic testing the national and supranational protection of minors could be strengthened by approving guidelines based on a common framework of principles and values. We suggest that the Oviedo Convention could represent an example of such a common framework or, at least, it could lead to articulate it. PMID:22567400

Improving Disease Prediction by Incorporating Family Disease History in Risk Prediction Models with Large-Scale Genetic Data.

PubMed

Gim, Jungsoo; Kim, Wonji; Kwak, Soo Heon; Choi, Hosik; Park, Changyi; Park, Kyong Soo; Kwon, Sunghoon; Park, Taesung; Won, Sungho

2017-11-01

Despite the many successes of genome-wide association studies (GWAS), the known susceptibility variants identified by GWAS have modest effect sizes, leading to notable skepticism about the effectiveness of building a risk prediction model from large-scale genetic data. However, in contrast to genetic variants, the family history of diseases has been largely accepted as an important risk factor in clinical diagnosis and risk prediction. Nevertheless, the complicated structures of the family history of diseases have limited their application in clinical practice. Here, we developed a new method that enables incorporation of the general family history of diseases with a liability threshold model, and propose a new analysis strategy for risk prediction with penalized regression analysis that incorporates both large numbers of genetic variants and clinical risk factors. Application of our model to type 2 diabetes in the Korean population (1846 cases and 1846 controls) demonstrated that single-nucleotide polymorphisms accounted for 32.5% of the variation explained by the predicted risk scores in the test data set, and incorporation of family history led to an additional 6.3% improvement in prediction. Our results illustrate that family medical history provides valuable information on the variation of complex diseases and improves prediction performance. Copyright © 2017 by the Genetics Society of America.

Effects of functionally asexual reproduction on quantitative genetic variation in the evening primroses (Oenothera, Onagraceae).

PubMed

Godfrey, Ryan M; Johnson, Marc T J

2014-11-01

It has long been predicted that a loss of sexual reproduction leads to decreased heritable variation within populations and increased differentiation between populations. Despite an abundance of theory, there are few empirical tests of how sex affects genetic variation in phenotypic traits, especially for plants. Here we test whether repeated losses of two critical components of sex (recombination and segregation) in the evening primroses (Oenothera L., Onagraceae) affect quantitative genetic variation within and between populations. We sampled multiple genetic families from 3-5 populations from each of eight Oenothera species, which represented four independent transitions between sexual reproduction and a functionally asexual genetic system called "permanent translocation heterozygosity." We used quantitative genetics methods to partition genetic variation within and between populations for eight plant traits related to growth, leaf physiology, flowering, and resistance to herbivores. Heritability was, on average, 74% higher in sexual Oenothera populations than in functionally asexual populations, with plant growth rate, specific leaf area, and the percentage of leaf water content showing the strongest differences. By contrast, genetic differentiation among populations was 2.8× higher in functionally asexual vs. sexual Oenothera species. This difference was particularly strong for specific leaf area. Sexual populations tended to exhibit higher genetic correlations among traits, but this difference was weakly supported. These results support the prediction that sexual reproduction maintains higher genetic variation within populations, which may facilitate adaptive evolution. We also found partial support for the prediction that a loss of sex leads to greater population differentiation, which may elevate speciation rates. © 2014 Botanical Society of America, Inc.

Exploring dispositional tendencies to seek online information about direct-to-consumer genetic testing.

PubMed

Paquin, Ryan S; Richards, Adam S; Koehly, Laura M; McBride, Colleen M

2012-12-01

Varying perspectives exist regarding the implications of genetic susceptibility testing for common disease, with some anticipating adverse effects and others expecting positive outcomes; however, little is known about the characteristics of people who are most likely to be interested in direct-to-consumer genetic testing. To that end, this study examines the association of individual dispositional differences with health risk perceptions and online information seeking related to a free genetic susceptibility test. Healthy adults enrolled in a large health maintenance organization were surveyed by telephone. Eligible participants (N = 1,959) were given access to a secure website that provided risk and benefit information about a genetic susceptibility test and given the option to be tested. Neuroticism was associated with increased perceptions of disease risk but not with logging on. Those scoring high in conscientiousness were more likely to log on. We found no evidence that neuroticism, a dispositional characteristic commonly linked to adverse emotional response, was predictive of online genetic information seeking in this sample of healthy adults.

Public reaction to direct-to-consumer online genetic tests: Comparing attitudes, trust and intentions across commercial and conventional providers.

PubMed

Critchley, Christine; Nicol, Dianne; Otlowski, Margaret; Chalmers, Don

2015-08-01

The success of personalised medicine depends upon the public's embracing genetic tests. Tests that claim to predict an individual's future health can now be accessed via online companies outside of conventional health regulations. This research assessed the extent to which the public embrace direct-to-consumer (DTC) genetic tests relative to those obtained by a conventional medical practitioner (MP). It also examined the reasons for differences across providers using a randomised experimental telephone survey of 1000 Australians. Results suggest that people were significantly less likely to approve of, and order a DTC genetic test administered by a company compared to a MP because they were less trusting of companies' being able to protect their privacy and provide them with access to genetic expertise and counselling. Markets for DTC genetic tests provided by companies would therefore significantly increase if trust in privacy protection and access to expertise are enhanced through regulation. © The Author(s) 2014.

A test of genetic models for the evolutionary maintenance of same-sex sexual behaviour.

PubMed

Hoskins, Jessica L; Ritchie, Michael G; Bailey, Nathan W

2015-06-22

The evolutionary maintenance of same-sex sexual behaviour (SSB) has received increasing attention because it is perceived to be an evolutionary paradox. The genetic basis of SSB is almost wholly unknown in non-human animals, though this is key to understanding its persistence. Recent theoretical work has yielded broadly applicable predictions centred on two genetic models for SSB: overdominance and sexual antagonism. Using Drosophila melanogaster, we assayed natural genetic variation for male SSB and empirically tested predictions about the mode of inheritance and fitness consequences of alleles influencing its expression. We screened 50 inbred lines derived from a wild population for male-male courtship and copulation behaviour, and examined crosses between the lines for evidence of overdominance and antagonistic fecundity selection. Consistent variation among lines revealed heritable genetic variation for SSB, but the nature of the genetic variation was complex. Phenotypic and fitness variation was consistent with expectations under overdominance, although predictions of the sexual antagonism model were also supported. We found an unexpected and strong paternal effect on the expression of SSB, suggesting possible Y-linkage of the trait. Our results inform evolutionary genetic mechanisms that might maintain low but persistently observed levels of male SSB in D. melanogaster, but highlight a need for broader taxonomic representation in studies of its evolutionary causes. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Genetic parameters for milk mineral content and acidity predicted by mid-infrared spectroscopy in Holstein-Friesian cows.

PubMed

Toffanin, V; Penasa, M; McParland, S; Berry, D P; Cassandro, M; De Marchi, M

2015-05-01

The aim of the present study was to estimate genetic parameters for calcium (Ca), phosphorus (P) and titratable acidity (TA) in bovine milk predicted by mid-IR spectroscopy (MIRS). Data consisted of 2458 Italian Holstein-Friesian cows sampled once in 220 farms. Information per sample on protein and fat percentage, pH and somatic cell count, as well as test-day milk yield, was also available. (Co)variance components were estimated using univariate and bivariate animal linear mixed models. Fixed effects considered in the analyses were herd of sampling, parity, lactation stage and a two-way interaction between parity and lactation stage; an additive genetic and residual term were included in the models as random effects. Estimates of heritability for Ca, P and TA were 0.10, 0.12 and 0.26, respectively. Positive moderate to strong phenotypic correlations (0.33 to 0.82) existed between Ca, P and TA, whereas phenotypic weak to moderate correlations (0.00 to 0.45) existed between these traits with both milk quality and yield. Moderate to strong genetic correlations (0.28 to 0.92) existed between Ca, P and TA, and between these predicted traits with both fat and protein percentage (0.35 to 0.91). The existence of heritable genetic variation for Ca, P and TA, coupled with the potential to predict these components for routine cow milk testing, imply that genetic gain in these traits is indeed possible.

Diallel analysis for sex-linked and maternal effects.

PubMed

Zhu, J; Weir, B S

1996-01-01

Genetic models including sex-linked and maternal effects as well as autosomal gene effects are described. Monte Carlo simulations were conducted to compare efficiencies of estimation by minimum norm quadratic unbiased estimation (MINQUE) and restricted maximum likelihood (REML) methods. MINQUE(1), which has 1 for all prior values, has a similar efficiency to MINQUE(θ), which requires prior estimates of parameter values. MINQUE(1) has the advantage over REML of unbiased estimation and convenient computation. An adjusted unbiased prediction (AUP) method is developed for predicting random genetic effects. AUP is desirable for its easy computation and unbiasedness of both mean and variance of predictors. The jackknife procedure is appropriate for estimating the sampling variances of estimated variances (or covariances) and of predicted genetic effects. A t-test based on jackknife variances is applicable for detecting significance of variation. Worked examples from mice and silkworm data are given in order to demonstrate variance and covariance estimation and genetic effect prediction.

Genetic Testing and Neuroimaging for Youth at Risk for Mental Illness: Trading off Benefit and Risk.

PubMed

Lee, Grace; Mizgalewicz, Ania; Borgelt, Emily; Illes, Judy

2015-01-01

According to the World Health Organization, mental illness is one of the leading causes of disability worldwide. The first onset of mental illness usually occurs during childhood or adolescence, with nearly 12 million diagnosed cases in the United States alone. Neuroimaging and genetic testing have been invaluable in research on behavioral, affective, and attentional disorders, particularly with their potential predictive capabilities, and ability to improve diagnosis and to decrease the associated burdens of disease. The present study focused specifically the perspectives of mental health providers on the role of neuroimaging and genetic testing in clinical practice with children and adolescents. We interviewed 38 psychiatrists, psychologists, and allied mental health professionals who work primarily with youth about their receptivity toward either the use of neuroimaging or genetic testing. Interviews probed the role they foresee for these modalities for prediction, diagnosis, treatment planning, and the benefits and risks they anticipate. Practitioners anticipated three major benefits associated with clinical introduction of imaging and genetic testing in the mental health care for youth: (1) improved understanding of the brain and mental illness, (2) more accurate diagnosis than available through conventional clinical examination, and (3) legitimization of treatment plans. They also perceived three major risks: (1) misuse or misinterpretation of the imaging or genetic data, (2) potential adverse impacts on employment and insurance as adolescents reach adulthood, and (3) infringements on self-esteem or self-motivation. The nature of the interview questions focused on the future of neuroimaging and genetic testing testing research in the context of clinical neuroscience. Therefore, the responses from interview participants are based on anticipated rather than actual experience. Continued expansion of brain imaging and genetic testing into clinical care will require a delicate balance of brain biology and respect for autonomy in the still-evolving cognitive and affective world of young individuals.

Ethical issues in neurogenetics.

PubMed

Uhlmann, Wendy R; Roberts, J Scott

2018-01-01

Many neurogenetic conditions are inherited and therefore diagnosis of a patient will have implications for the patient's relatives and can raise ethical issues. Predictive genetic testing offers asymptomatic relatives the opportunity to determine their risk status for a neurogenetic condition, and professional guidelines emphasize patients' autonomy and informed, voluntary decision making. Beneficence and nonmaleficence both need to be considered when making decisions about disclosure and nondisclosure of genetic information and test results. There can be disclosure concerns and challenges in determining whose autonomy to prioritize when a patient makes a genetic testing decision that can reveal the genetic status of a relative (e.g., testing an adult child when the at-risk parent has not been tested). Ethical issues are prominent when genetic testing for neurogenetic conditions is requested prenatally, on minors, adoptees, adult children at 25% risk, and for individuals with psychiatric issues or cognitive impairment. Neurogenetic conditions can result in cognitive decline which can affect decisional capacity and lead to ethical challenges with decision making, informed consent, and determining the patient's ability to comprehend test results. The ethical implications of genetic testing and emerging issues, including direct-to-consumer genetic testing, disclosure of secondary findings from genomic sequencing, and use of apolipoprotein E testing in clinical and research settings, are also discussed. Resources for information about genetic testing practice guidelines, insurance laws, and directories of genetics clinics are included. Copyright © 2018 Elsevier B.V. All rights reserved.

Ethical Issues in Neurogenetics

PubMed Central

Uhlmann, Wendy R.; Roberts, J. Scott

2018-01-01

Many neurogenetic conditions are inherited and therefore diagnosis of a patient will have implications for their relatives and can raise ethical issues. Predictive genetic testing offers asymptomatic relatives the opportunity to determine their risk status for a neurogenetic condition, and professional guidelines emphasize patients’ autonomy and informed, voluntary decision-making. Beneficence and non-maleficence both need to be considered when making decisions about disclosure and nondisclosure of genetic information and test results. There can be disclosure concerns and issues of determining whose autonomy to prioritize when a patient makes a genetic testing decision that can reveal the genetic status of a relative (e.g. testing an adult child when the at-risk parent has not been tested). Ethical issues are prominent when genetic testing for neurogenetic conditions is requested prenatally, on minors, adoptees, adult children at 25% risk, and for individuals with psychiatric issues or cognitive impairment. Neurogenetic conditions can result in cognitive decline which can affect decisional capacity and lead to ethical challenges with decision-making, informed consent and determining the patient’s ability to comprehend test results. The ethical implications of genetic testing and emerging issues, including direct-to-consumer genetic testing, disclosure of secondary findings from genomic sequencing, and use of APOE testing in clinical and research settings, are also discussed. Resources for information about genetic testing practice guidelines, insurance laws and directories of genetics clinics are included. PMID:29325614

Discriminatory power of common genetic variants in personalized breast cancer diagnosis

NASA Astrophysics Data System (ADS)

Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

2016-03-01

Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

Integrating paleoecology and genetics of bird populations in two sky island archipelagos

PubMed Central

McCormack, John E; Bowen, Bonnie S; Smith, Thomas B

2008-01-01

Background Genetic tests of paleoecological hypotheses have been rare, partly because recent genetic divergence is difficult to detect and time. According to fossil plant data, continuous woodland in the southwestern USA and northern Mexico became fragmented during the last 10,000 years, as warming caused cool-adapted species to retreat to high elevations. Most genetic studies of resulting 'sky islands' have either failed to detect recent divergence or have found discordant evidence for ancient divergence. We test this paleoecological hypothesis for the region with intraspecific mitochondrial DNA and microsatellite data from sky-island populations of a sedentary bird, the Mexican jay (Aphelocoma ultramarina). We predicted that populations on different sky islands would share common, ancestral alleles that existed during the last glaciation, but that populations on each sky island, owing to their isolation, would contain unique variants of postglacial origin. We also predicted that divergence times estimated from corrected genetic distance and a coalescence model would post-date the last glacial maximum. Results Our results provide multiple independent lines of support for postglacial divergence, with the predicted pattern of shared and unique mitochondrial DNA haplotypes appearing in two independent sky-island archipelagos, and most estimates of divergence time based on corrected genetic distance post-dating the last glacial maximum. Likewise, an isolation model based on multilocus gene coalescence indicated postglacial divergence of five pairs of sky islands. In contrast to their similar recent histories, the two archipelagos had dissimilar historical patterns in that sky islands in Arizona showed evidence for older divergence, suggesting different responses to the last glaciation. Conclusion This study is one of the first to provide explicit support from genetic data for a postglacial divergence scenario predicted by one of the best paleoecological records in the world. Our results demonstrate that sky islands act as generators of genetic diversity at both recent and historical timescales and underscore the importance of thorough sampling and the use of loci with fast mutation rates to studies that test hypotheses concerning recent genetic divergence. PMID:18588695

Confidentiality, privacy, and security of genetic and genomic test information in electronic health records: points to consider.

PubMed

McGuire, Amy L; Fisher, Rebecca; Cusenza, Paul; Hudson, Kathy; Rothstein, Mark A; McGraw, Deven; Matteson, Stephen; Glaser, John; Henley, Douglas E

2008-07-01

As clinical genetics evolves, and we embark down the path toward more personalized and effective health care, the amount, detail, and complexity of genetic/genomic test information within the electronic health record will increase. This information should be appropriately protected to secure the trust of patients and to support interoperable electronic health information exchange. This article discusses characteristics of genetic/genomic test information, including predictive capability, immutability, and uniqueness, which should be considered when developing policies about information protection. Issues related to "genetic exceptionalism"; i.e., whether genetic/genomic test information should be treated differently from other medical information for purposes of data access and permissible use, are also considered. These discussions can help guide policy that will facilitate the biological and clinical resource development to support the introduction of this information into health care.

Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? Rotterdam Leiden Genetics Workgroup.

PubMed Central

DudokdeWit, A C; Tibben, A; Duivenvoorden, H J; Niermeijer, M F; Passchier, J

1998-01-01

The first comparative study on predicting post-test distress (conceptualised by intrusion and avoidance, measured with the Impact of Event Scale) after presymptomatic genetic testing for Huntington's disease (HD, n=25), cancer syndromes (familial adenomatous polyposis (FAP, n=23)), and hereditary breast and ovarian cancer (HBOC, n=10) is reported. The variables with the highest predictive potential of post-test distress are presented. Participants who were depressed before the test were more distressed after testing, but we found that those who were anxious before the test were less distressed, that is, had less intrusive thoughts post-test. Other factors associated with a higher level of post-test intrusion were gender (being a woman), having children, and pre-test intrusion. Religion and being at risk for HBOC were associated with less post-test intrusion. Participants who showed avoidance behaviour before the test and those who had many people available for support showed more avoidance behaviour post-test. The test result did not additionally contribute to post-test distress. The prima facie simple notion that the test result, as such, determines the distress experienced seems to be a misrepresentation of the complex reality. PMID:9733033

Landscape attributes and life history variability shape genetic structure of trout populations in a stream network

USGS Publications Warehouse

Neville, H.M.; Dunham, J.B.; Peacock, M.M.

2006-01-01

Spatial and temporal landscape patterns have long been recognized to influence biological processes, but these processes often operate at scales that are difficult to study by conventional means. Inferences from genetic markers can overcome some of these limitations. We used a landscape genetics approach to test hypotheses concerning landscape processes influencing the demography of Lahontan cutthroat trout in a complex stream network in the Great Basin desert of the western US. Predictions were tested with population- and individual-based analyses of microsatellite DNA variation, reflecting patterns of dispersal, population stability, and local effective population sizes. Complementary genetic inferences suggested samples from migratory corridors housed a mixture of fish from tributaries, as predicted based on assumed migratory life histories in those habitats. Also as predicted, populations presumed to have greater proportions of migratory fish or from physically connected, large, or high quality habitats had higher genetic variability and reduced genetic differentiation from other populations. Populations thought to contain largely non-migratory individuals generally showed the opposite pattern, suggesting behavioral isolation. Estimated effective sizes were small, and we identified significant and severe genetic bottlenecks in several populations that were isolated, recently founded, or that inhabit streams that desiccate frequently. Overall, this work suggested that Lahontan cutthroat trout populations in stream networks are affected by a combination of landscape and metapopulation processes. Results also demonstrated that genetic patterns can reveal unexpected processes, even within a system that is well studied from a conventional ecological perspective. ?? Springer 2006.

Support Seeking or Familial Obligation: An Investigation of Motives for Disclosing Genetic Test Results

PubMed Central

Greenberg, Marisa; Smith, Rachel A.

2016-01-01

Genetic test results reveal not only personal information about a person’s likelihood of certain medical conditions but also information about their genetic relatives (Annas, Glantz, & Roche, 1995). Given the familial nature of genetic information, one’s obligation to protect family members may be a motive for disclosing genetic test results, but this claim has not been methodically tested. Existing models of disclosure decision-making presume self-interested motives, such as seeking social support, instead of other-interested motives, like familial obligation. This study investigated young adults’ (N = 173) motives to share a genetic-based health condition, alpha-1 antitrypsin deficiency, after reading a hypothetical vignette. Results show that social support and familial obligation were both reported as motives for disclosure. In fact, some participants reported familial obligation as their primary motivator for disclosure. Finally, stronger familial obligation predicted increased likelihood of disclosing hypothetical genetic test results. Implications of these results were discussed in reference to theories of disclosure decision-making models and the practice of genetic disclosures. PMID:26507777

Genetic and life-history consequences of extreme climate events

PubMed Central

Mangel, Marc; Jesensek, Dusan; Garza, John Carlos; Crivelli, Alain J.

2017-01-01

Climate change is predicted to increase the frequency and intensity of extreme climate events. Tests on empirical data of theory-based predictions on the consequences of extreme climate events are thus necessary to understand the adaptive potential of species and the overarching risks associated with all aspects of climate change. We tested predictions on the genetic and life-history consequences of extreme climate events in two populations of marble trout Salmo marmoratus that have experienced severe demographic bottlenecks due to flash floods. We combined long-term field and genotyping data with pedigree reconstruction in a theory-based framework. Our results show that after flash floods, reproduction occurred at a younger age in one population. In both populations, we found the highest reproductive variance in the first cohort born after the floods due to a combination of fewer parents and higher early survival of offspring. A small number of parents allowed for demographic recovery after the floods, but the genetic bottleneck further reduced genetic diversity in both populations. Our results also elucidate some of the mechanisms responsible for a greater prevalence of faster life histories after the extreme event. PMID:28148745

Engagement with genetic discrimination: concerns and experiences in the context of Huntington disease

PubMed Central

Bombard, Yvonne; Penziner, Elizabeth; Suchowersky, Oksana; Guttman, Mark; Paulsen, Jane S; Bottorff, Joan L; Hayden, Michael R

2013-01-01

It has been over 20 years since the inception of predictive testing for Huntington disease (HD), yet the social implications of knowing one's genetic risk for HD have not been fully explored. Genetic discrimination (GD) is a potential risk associated with predictive testing. Although anecdotal reports of GD have been documented, there is a paucity of research on the nature and experiences of GD in the context of HD. The purpose of this study was to describe the concerns and experiences of GD in the HD community. Semistructured interviews were conducted with 45 genetically tested and 10 untested individuals and analyzed using grounded theory methods. Our findings demonstrate that a majority of individuals were concerned about (37/55) and experienced GD (32/55) across a variety of contexts that extend beyond the traditionally examined contexts of insurance and employment to include family, social, government, and health-care domains. We describe a process of engagement with GD in which individuals formed meaningful interpretations of GD and personalized its risk and consequences in their lives. Our findings provide an insight into some of the specific processes and factors influencing engagement with GD. These results help identify areas where more education and support is needed and provide direction to genetic professionals supporting their clients as they confront issues of GD and genetic testing. PMID:17957229

A Genetic Test Predicts Providence Brace Success for Adolescent Idiopathic Scoliosis When Failure Is Defined as Progression to >45 Degrees.

PubMed

Bohl, Daniel D; Telles, Connor J; Ruiz, Ferrin K; Badrinath, Raghav; DeLuca, Peter A; Grauer, Jonathan N

2016-04-01

Retrospective cohort. To determine whether a genetic test is associated with successful Providence bracing for adolescent idiopathic scoliosis (AIS). Genetic factors have been defined that predict the risk of progression of AIS in a polygenic fashion. From these data, a commercially available genetic test, ScoliScore, was developed. It is now used in clinical practice for counseling and to guide clinical management. Bracing is a mainstay of treatment for AIS. Large efforts have been made recently to reduce potential confounding across studies of different braces; however, none of these have considered genetics as a potential confounder. In particular, ScoliScore has not been evaluated in a population undergoing bracing. We conducted a retrospective cohort study in which we identified a population of AIS patients who were initiated with Providence bracing and followed over time. Although these patients did not necessarily fit the commercial indications for ScoliScore, we contacted the patients and obtained a saliva sample from each for genetic analysis. We then tested whether ScoliScore correlated with the outcome of their bracing therapy. We were able to contact and invite 25 eligible subjects, of whom 16 (64.0%) returned samples for laboratory analysis. Patients were followed for an average of 2.3 years (range, 1.1-4 y) after initiation of the Providence brace. Eight patients (50.0%) progressed to >45 degrees, whereas the other 8 patients (50.0%) did not. The mean ScoliScore among those who progressed to >45 degrees was higher than that among those who did not (176 vs. 112, P=0.030). We demonstrate that a genetic test correlates with bracing outcome. It may be appropriate for future bracing studies to include analysis of genetic predisposition to limit potential confounding.

Privacy-preserving genomic testing in the clinic: a model using HIV treatment

PubMed Central

McLaren, Paul J.; Raisaro, Jean Louis; Aouri, Manel; Rotger, Margalida; Ayday, Erman; Bartha, István; Delgado, Maria B.; Vallet, Yannick; Günthard, Huldrych F.; Cavassini, Matthias; Furrer, Hansjakob; Doco-Lecompte, Thanh; Marzolini, Catia; Schmid, Patrick; Di Benedetto, Caroline; Decosterd, Laurent A.; Fellay, Jacques; Hubaux, Jean-Pierre; Telenti, Amalio

2016-01-01

Purpose: The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics. Genet Med 18 8, 814–822. Methods: We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers. Genet Med 18 8, 814–822. Results: A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%. Genet Med 18 8, 814–822. Conclusions: The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine. Genet Med 18 8, 814–822. PMID:26765343

Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects

PubMed Central

Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A.

2016-01-01

The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates’ offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of “half-sibling” in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure. PMID:26801647

Genetic determinants of freckle occurrence in the Spanish population: Towards ephelides prediction from human DNA samples.

PubMed

Hernando, Barbara; Ibañez, Maria Victoria; Deserio-Cuesta, Julio Alberto; Soria-Navarro, Raquel; Vilar-Sastre, Inca; Martinez-Cadenas, Conrado

2018-03-01

Prediction of human pigmentation traits, one of the most differentiable externally visible characteristics among individuals, from biological samples represents a useful tool in the field of forensic DNA phenotyping. In spite of freckling being a relatively common pigmentation characteristic in Europeans, little is known about the genetic basis of this largely genetically determined phenotype in southern European populations. In this work, we explored the predictive capacity of eight freckle and sunlight sensitivity-related genes in 458 individuals (266 non-freckled controls and 192 freckled cases) from Spain. Four loci were associated with freckling (MC1R, IRF4, ASIP and BNC2), and female sex was also found to be a predictive factor for having a freckling phenotype in our population. After identifying the most informative genetic variants responsible for human ephelides occurrence in our sample set, we developed a DNA-based freckle prediction model using a multivariate regression approach. Once developed, the capabilities of the prediction model were tested by a repeated 10-fold cross-validation approach. The proportion of correctly predicted individuals using the DNA-based freckle prediction model was 74.13%. The implementation of sex into the DNA-based freckle prediction model slightly improved the overall prediction accuracy by 2.19% (76.32%). Further evaluation of the newly-generated prediction model was performed by assessing the model's performance in a new cohort of 212 Spanish individuals, reaching a classification success rate of 74.61%. Validation of this prediction model may be carried out in larger populations, including samples from different European populations. Further research to validate and improve this newly-generated freckle prediction model will be needed before its forensic application. Together with DNA tests already validated for eye and hair colour prediction, this freckle prediction model may lead to a substantially more detailed physical description of unknown individuals from DNA found at the crime scene. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic parameters of blood β-hydroxybutyrate predicted from milk infrared spectra and clinical ketosis, and their associations with milk production traits in Norwegian Red cows.

PubMed

Belay, T K; Svendsen, M; Kowalski, Z M; Ådnøy, T

2017-08-01

The aim of this study was to estimate genetic parameters for blood β-hydroxybutyrate (BHB) predicted from milk spectra and for clinical ketosis (KET), and to examine genetic association of blood BHB with KET and milk production traits (milk, fat, protein, and lactose yields, and milk fat, protein, and lactose contents). Data on milk traits, KET, and milk spectra were obtained from the Norwegian Dairy Herd Recording System with legal permission from TINE SA (Ås, Norway), the Norwegian Dairy Association that manages the central database. Data recorded up to 120 d after calving were considered. Blood BHB was predicted from milk spectra using a calibration model developed based on milk spectra and blood BHB measured in Polish dairy cows. The predicted blood BHB was grouped based on days in milk into 4 groups and each group was considered as a trait. The milk components for test-day milk samples were obtained by Fourier transform mid-infrared spectrometer with previously developed calibration equations from Foss (Hillerød, Denmark). Veterinarian-recorded KET data within 15 d before calving to 120 d after calving were used. Data were analyzed using univariate or bivariate linear animal models. Heritability estimates for predicted blood BHB at different stages of lactation were moderate, ranging from 0.250 to 0.365. Heritability estimate for KET from univariate analysis was 0.078, and the corresponding average estimate from bivariate analysis with BHB or milk production traits was 0.002. Genetic correlations between BHB traits were higher for adjacent lactation intervals and decreased as intervals were further apart. Predicted blood BHB at first test day was moderately genetically correlated with KET (0.469) and milk traits (ranged from -0.367 with protein content to 0.277 with milk yield), except for milk fat content from across lactation stages that had near zero genetic correlation with BHB (0.033). These genetic correlations indicate that a lower BHB is genetically associated with higher milk protein and lactose contents, but with lower yields of milk, fat, protein, and lactose, and with lower frequency of KET. Estimates of genetic correlation of KET with milk production traits were from -0.333 (with protein content) to 0.178 (with milk yield). Blood BHB can routinely be predicted from milk spectra analyzed from test-day milk samples, and thereby provides a practical alternative for selecting cows with lower susceptibility to ketosis, even though the correlations are moderate. The Authors. Published by the Federation of Animal Science Societies and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Explaining, not just predicting, drives interest in personal genomics.

PubMed

Meisel, Susanne F; Carere, Deanna Alexis; Wardle, Jane; Kalia, Sarah S; Moreno, Tanya A; Mountain, Joanna L; Roberts, J Scott; Green, Robert C

2015-01-01

There is a widespread assumption that risk prediction is the major driver of customer interest in personal genomic testing (PGT). However, some customers may also be motivated by finding out whether their existing diseases have a genetic etiology. We evaluated the impact of an existing medical diagnosis on customer interest in condition-specific results from PGT. Using a prospective online survey of PGT customers, we measured customer interest prior to receiving PGT results for 11 health conditions, and examined the association between interest and personal medical history of these conditions using logistic regression. We analyzed data from 1,538 PGT customers, mean age 48.7 years, 61 % women, 90 % White, and 47 % college educated. The proportion of customers who were 'very interested' in condition-specific PGT varied considerably, from 28 % for ulcerative colitis to 68% for heart disease. After adjusting for demographic and personal characteristics including family history, having a diagnosis of the condition itself was significantly associated with interest in genetic testing for risk of that condition, with odds ratios ranging from 2.07 (95 % CI 1.28-3.37) for diabetes to 19.99 (95 % CI 4.57-87.35) for multiple sclerosis. PGT customers are particularly interested in genetic markers for their existing medical conditions, suggesting that the value of genetic testing is not only predictive, but also explanatory.

Prediction of Aerodynamic Coefficients for Wind Tunnel Data using a Genetic Algorithm Optimized Neural Network

NASA Technical Reports Server (NTRS)

Rajkumar, T.; Aragon, Cecilia; Bardina, Jorge; Britten, Roy

2002-01-01

A fast, reliable way of predicting aerodynamic coefficients is produced using a neural network optimized by a genetic algorithm. Basic aerodynamic coefficients (e.g. lift, drag, pitching moment) are modelled as functions of angle of attack and Mach number. The neural network is first trained on a relatively rich set of data from wind tunnel tests of numerical simulations to learn an overall model. Most of the aerodynamic parameters can be well-fitted using polynomial functions. A new set of data, which can be relatively sparse, is then supplied to the network to produce a new model consistent with the previous model and the new data. Because the new model interpolates realistically between the sparse test data points, it is suitable for use in piloted simulations. The genetic algorithm is used to choose a neural network architecture to give best results, avoiding over-and under-fitting of the test data.

Personal Factors Associated with Reported Benefits of Huntington Disease Family History or Genetic Testing

PubMed Central

Williams, Janet K.; Erwin, Cheryl; Juhl, Andrew; Mills, James; Brossman, Bradley

2010-01-01

Aims: A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. Methods: Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I-RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spirituality were significantly associated with benefits in both groups. Conclusions: Perceptions of benefit may not be as likely until later years in people with prodromal HD. A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD. Associations among spirituality, perceived benefits, and other indicators of personal and family well-being may be useful in genetic counseling and health care of people with prodromal HD. PMID:20722493

Impact of Huntington Disease Gene-Positive Status on Pre-Symptomatic Young Adults and Recommendations for Genetic Counselors.

PubMed

Gong, Ping; Fanos, Joanna H; Korty, Lauren; Siskind, Carly E; Hanson-Kahn, Andrea K

2016-12-01

Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder for which there is no cure. Predictive testing for HD is available to asymptomatic at-risk individuals. Approximately half of the population undergoing predictive testing for HD consists of young adults (≤35 years old). Finishing one's education, starting a career, engaging in romantic relationships and becoming a parent are key milestones of young adulthood. We conducted a qualitative study to explore how testing gene-positive for HD influences young adults' attainment of these milestones, and to identify major challenges that pre-symptomatic young adults face to aid the development of targeted genetic counseling. Results of our study demonstrate that 1) knowing one's gene-positive status results in an urgency to reach milestones and positively changes young adults' approach to life; 2) testing positive influences young adults' education and career choices, romantic relationships, and family planning; 3) young adults desire flexible and tailored genetic counseling to address needs and concerns unique to this population. Findings of this study contribute to the understanding of the impact of predictive testing for HD on young adults, and highlight issues unique to this population that call for further research, intervention and advocacy.

Feline Genetics: Clinical Applications and Genetic Testing

PubMed Central

Lyons, Leslie A.

2010-01-01

DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately thirty-three genes contain fifty mutations that cause feline health problems or alterations in the cat’s appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab using a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat’s internal genome. PMID:21147473

Feline genetics: clinical applications and genetic testing.

PubMed

Lyons, Leslie A

2010-11-01

DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome. Copyright © 2010 Elsevier Inc. All rights reserved.

Modifications to the Patient Rule-Induction Method that utilize non-additive combinations of genetic and environmental effects to define partitions that predict ischemic heart disease.

PubMed

Dyson, Greg; Frikke-Schmidt, Ruth; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne; Sing, Charles F

2009-05-01

This article extends the Patient Rule-Induction Method (PRIM) for modeling cumulative incidence of disease developed by Dyson et al. (Genet Epidemiol 31:515-527) to include the simultaneous consideration of non-additive combinations of predictor variables, a significance test of each combination, an adjustment for multiple testing and a confidence interval for the estimate of the cumulative incidence of disease in each partition. We employ the partitioning algorithm component of the Combinatorial Partitioning Method to construct combinations of predictors, permutation testing to assess the significance of each combination, theoretical arguments for incorporating a multiple testing adjustment and bootstrap resampling to produce the confidence intervals. An illustration of this revised PRIM utilizing a sample of 2,258 European male participants from the Copenhagen City Heart Study is presented that assesses the utility of genetic variants in predicting the presence of ischemic heart disease beyond the established risk factors.

Ethical and clinical practice considerations for genetic counselors related to direct-to-consumer marketing of genetic tests.

PubMed

Wade, Christopher H; Wilfond, Benjamin S

2006-11-15

Several companies utilize direct-to-consumer (DTC) advertising for genetic tests and some, but not all, bypass clinician involvement by offering DTC purchase of the tests. This article examines how DTC marketing strategies may affect genetic counselors, using available cardiovascular disease susceptibility tests as an illustration. The interpretation of these tests is complex and includes consideration of clinical validity and utility, and the further complications of gene-environment interactions and pleiotropy. Although it is unclear to what extent genetic counselors will encounter clients who have been exposed to DTC marketing strategies, these strategies may influence genetic counseling interactions if they produce directed interest in specific tests and unrealistic expectations for the tests' capacity to predict disease. Often, a client's concern about risk for cardiovascular diseases is best addressed by established clinical tests and a family history assessment. Ethical dilemmas may arise for genetic counselors who consider whether to accept clients who request test interpretation or to order DTC-advertised tests that require a clinician's authorization. Genetic counselors' obligations to care for clients extend to interpreting DTC tests, although this obligation may be fulfilled by referral or consultation with specialists. Genetic counselors do not have an obligation to order DTC-advertised tests that have minimal clinical validity and utility at a client's request. This can be a justified restriction on autonomy based on consideration of risks to the client, the costs, and the implications for society. Published 2006 Wiley-Liss, Inc.

Genetic analysis of groups of mid-infrared predicted fatty acids in milk.

PubMed

Narayana, S G; Schenkel, F S; Fleming, A; Koeck, A; Malchiodi, F; Jamrozik, J; Johnston, J; Sargolzaei, M; Miglior, F

2017-06-01

The objective of this study was to investigate genetic variability of mid-infrared predicted fatty acid groups in Canadian Holstein cattle. Genetic parameters were estimated for 5 groups of fatty acids: short-chain (4 to 10 carbons), medium-chain (11 to 16 carbons), long-chain (17 to 22 carbons), saturated, and unsaturated fatty acids. The data set included 49,127 test-day records from 10,029 first-lactation Holstein cows in 810 herds. The random regression animal test-day model included days in milk, herd-test date, and age-season of calving (polynomial regression) as fixed effects, herd-year of calving, animal additive genetic effect, and permanent environment effects as random polynomial regressions, and random residual effect. Legendre polynomials of the third degree were selected for the fixed regression for age-season of calving effect and Legendre polynomials of the fourth degree were selected for the random regression for animal additive genetic, permanent environment, and herd-year effect. The average daily heritability over the lactation for the medium-chain fatty acid group (0.32) was higher than for the short-chain (0.24) and long-chain (0.23) fatty acid groups. The average daily heritability for the saturated fatty acid group (0.33) was greater than for the unsaturated fatty acid group (0.21). Estimated average daily genetic correlations were positive among all fatty acid groups and ranged from moderate to high (0.63-0.96). The genetic correlations illustrated similarities and differences in their origin and the makeup of the groupings based on chain length and saturation. These results provide evidence for the existence of genetic variation in mid-infrared predicted fatty acid groups, and the possibility of improving milk fatty acid profile through genetic selection in Canadian dairy cattle. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Direct-to-consumer advertising of predictive genetic tests: a health belief model based examination of consumer response.

PubMed

Rollins, Brent L; Ramakrishnan, Shravanan; Perri, Matthew

2014-01-01

Direct-to-consumer (DTC) advertising of predictive genetic tests (PGTs) has added a new dimension to health advertising. This study used an online survey based on the health belief model framework to examine and more fully understand consumers' responses and behavioral intentions in response to a PGT DTC advertisement. Overall, consumers reported moderate intentions to talk with their doctor and seek more information about PGTs after advertisement exposure, though consumers did not seem ready to take the advertised test or engage in active information search. Those who perceived greater threat from the disease, however, had significantly greater behavioral intentions and information search behavior.

Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism

PubMed Central

Wildenhain, Jan; Spitzer, Michaela; Dolma, Sonam; Jarvik, Nick; White, Rachel; Roy, Marcia; Griffiths, Emma; Bellows, David S.; Wright, Gerard D.; Tyers, Mike

2016-01-01

The network structure of biological systems suggests that effective therapeutic intervention may require combinations of agents that act synergistically. However, a dearth of systematic chemical combination datasets have limited the development of predictive algorithms for chemical synergism. Here, we report two large datasets of linked chemical-genetic and chemical-chemical interactions in the budding yeast Saccharomyces cerevisiae. We screened 5,518 unique compounds against 242 diverse yeast gene deletion strains to generate an extended chemical-genetic matrix (CGM) of 492,126 chemical-gene interaction measurements. This CGM dataset contained 1,434 genotype-specific inhibitors, termed cryptagens. We selected 128 structurally diverse cryptagens and tested all pairwise combinations to generate a benchmark dataset of 8,128 pairwise chemical-chemical interaction tests for synergy prediction, termed the cryptagen matrix (CM). An accompanying database resource called ChemGRID was developed to enable analysis, visualisation and downloads of all data. The CGM and CM datasets will facilitate the benchmarking of computational approaches for synergy prediction, as well as chemical structure-activity relationship models for anti-fungal drug discovery. PMID:27874849

Is Self-Regulation "All in the family"? Testing Environmental Effects using Within-Family Quasi-Experiments.

PubMed

Deater-Deckard, Kirby

2016-05-01

Most of the individual difference variance in the population is found within families, yet studying the processes causing this variation is difficult due to confounds between genetic and nongenetic influences. Quasi-experiments can be used to test hypotheses regarding environment exposure (e.g., timing, duration) while controlling for genetic confounds. To illustrate, two studies of cognitive self-regulation in childhood (i.e., working memory [WM], effortful control [EC], attention span/persistence [A/P]) are presented. Study 1 utilized an identical twin differences design ( N = 85 to 98 pairs) to control for genetic differences while using relative twin birth weight difference to predict relative twin difference in WM and EC. Larger relative twin difference in WM and EF was predicted by the combination of shorter gestation and larger relative birth weight difference. Study 2 utilized an adoptive sibling relative difference design ( N = 123 same-sex pairs) to control for genetic similarity while using relative sibling difference in the age at time of adoption to predict relative sibling difference in A/P. Larger relative sibling difference in A/P was predicted by the combination of larger relative difference in time in the adoptive home and age at adoption. Within-family quasi-experimental designs allow stronger inferences about hypothesized environmental influences than between-family designs permit.

Genetic prediction of type 2 diabetes using deep neural network.

PubMed

Kim, J; Kim, J; Kwak, M J; Bajaj, M

2018-04-01

Type 2 diabetes (T2DM) has strong heritability but genetic models to explain heritability have been challenging. We tested deep neural network (DNN) to predict T2DM using the nested case-control study of Nurses' Health Study (3326 females, 45.6% T2DM) and Health Professionals Follow-up Study (2502 males, 46.5% T2DM). We selected 96, 214, 399, and 678 single-nucleotide polymorphism (SNPs) through Fisher's exact test and L1-penalized logistic regression. We split each dataset randomly in 4:1 to train prediction models and test their performance. DNN and logistic regressions showed better area under the curve (AUC) of ROC curves than the clinical model when 399 or more SNPs included. DNN was superior than logistic regressions in AUC with 399 or more SNPs in male and 678 SNPs in female. Addition of clinical factors consistently increased AUC of DNN but failed to improve logistic regressions with 214 or more SNPs. In conclusion, we show that DNN can be a versatile tool to predict T2DM incorporating large numbers of SNPs and clinical information. Limitations include a relatively small number of the subjects mostly of European ethnicity. Further studies are warranted to confirm and improve performance of genetic prediction models using DNN in different ethnic groups. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Survey on the attitude toward genetic testing of neurologists certified by the Japanese Society of Neurology].

PubMed

Yoshida, Kunihiro; Ohata, Takako; Muto, Kaori; Tsuchiya, Atsushi; Sawada, Jinichi; Hazama, Takanori; Ikeda, Shu-Ichi; Toda, Tatsushi

2013-01-01

To clarify the attitude toward genetic testing for neuromuscular diseases, a questionnaire was sent to 4,762 neurologists certified by the Japanese Society of Neurology. By December 21, 2011, 1,493 questionnaires (31.4%) were returned. Of these, 1,233 (82.6%) had experienced genetic testing, but only 396 (26.5%) had referred to the guideline for genetic testing of the Japanese Society of Neurology (2009). The numbers of respondents who were positive, or more positive than negative for genetic testing for myotonic dystrophy type 1 (DM1), Huntington's disease (HD), and familial amyloid polyneuropathy (FAP) were 753 (50.4%), 915 (61.3%), and 980 (65.6%), respectively. The predominant reason for a positive attitude toward genetic testing was to confirm or exclude the diagnosis. Conversely, the predominant reason for a negative attitude toward genetic testing differed between the diseases. For DM1, it was to confirm the diagnosis without genetic testing. For HD, it was that genetic testing would not result in effective prevention or therapy. In FAP, it was that post-testing psychosocial support for the patient and their family was difficult. Common to DM1, HD, and FAP, a significant number of respondents (approximately 60%) felt it difficult to explain the negative aspects that might occur after the disclosure of test results. Concerning predictive or prenatal genetic testing, most respondents referred at-risk individuals to specialized genetic counseling clinics. In general, neurologists are likely to conduct genetic testing properly in consideration not only of the characteristics of the diseases but also of the circumstances of each patient and his or her family. To support neurologists who are involved in genetic testing, the guidelines should be more easily accessible. Many respondents wanted information on the institutions that provide genetic counseling and testing; however, financial support to such institutions is indispensable for fulfilling this requirement.

Commercialization of genetic testing services: the FDA, market forces, and biological tarot cards.

PubMed

Malinowski, M J; Blatt, R J R

1997-03-01

Many women fear being diagnosed with breast cancer, and rightfully so. Despite the capabilities of modern medicine, the cumulative lifetime risk of getting the disease has risen to one in eight and, despite decades of research, no cures exist. In this Article, the authors explore the commercialization of so-called breast cancer gene tests, based upon genetic alterations linked to the disease. Although the authors fully address this specific technology, they use what constitutes the seminal case of predictive genetic testing to analyze the adequacy of the existing regulatory framework. The authors conclude that the present regulatory system is inadequate and places a dangerous amount of reliance on primary care physicians. Their conclusion is grounded in the observation that most primary care physicians lack sufficient knowledge about this evolving investigative technology--which is highly subject to misinterpretation, and, though potentially helpful to some "high risk" patients, offers questionable clinical value for the general public. The authors set forth numerous proposals to promote both the quality and clinical value of predictive genetic testing so that it conforms to public health standards and can be properly integrated as a reliable component of medical care in specific situations.

Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia.

PubMed

Vallat, Laurent; Kemper, Corey A; Jung, Nicolas; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Meyer, Nicolas; Pocheville, Arnaud; Fisher, John W; Gribben, John G; Bahram, Seiamak

2013-01-08

Cellular behavior is sustained by genetic programs that are progressively disrupted in pathological conditions--notably, cancer. High-throughput gene expression profiling has been used to infer statistical models describing these cellular programs, and development is now needed to guide orientated modulation of these systems. Here we develop a regression-based model to reverse-engineer a temporal genetic program, based on relevant patterns of gene expression after cell stimulation. This method integrates the temporal dimension of biological rewiring of genetic programs and enables the prediction of the effect of targeted gene disruption at the system level. We tested the performance accuracy of this model on synthetic data before reverse-engineering the response of primary cancer cells to a proliferative (protumorigenic) stimulation in a multistate leukemia biological model (i.e., chronic lymphocytic leukemia). To validate the ability of our method to predict the effects of gene modulation on the global program, we performed an intervention experiment on a targeted gene. Comparison of the predicted and observed gene expression changes demonstrates the possibility of predicting the effects of a perturbation in a gene regulatory network, a first step toward an orientated intervention in a cancer cell genetic program.

Hereditary melanoma and predictive genetic testing: why not?

PubMed

Riedijk, S R; de Snoo, F A; van Dijk, S; Bergman, W; van Haeringen, A; Silberg, S; van Elderen, T M T; Tibben, A

2005-09-01

Since p16-Leiden presymptomatic testing for hereditary melanoma has become available in the Netherlands, the benefits and risks of offering such testing are evaluated. The current paper investigated why the non-participants were reluctant to participate in genetic testing. Sixty six eligible individuals, who were knowledgeable about the test but had not participated in genetic testing by January 2003, completed a self-report questionnaire assessing motivation, anxiety, family dynamics, risk knowledge and causal attributions. Non-participants reported anxiety levels below clinical significance. A principal components analysis on reasons for non-participation distinguished two underlying motives: emotional and rational motivation. Rational motivation for non-participation was associated with more accurate risk knowledge, the inclination to preselect mutation carriers within the family and lower scores on anxiety. Emotional motivation for non-participation was associated with disease misperceptions, hesitation to communicate unfavourable test results within the family and higher scores on anxiety. Rational and emotional motivation for non-participation in the genetic test for hereditary melanoma was found. Emotionally motivated individuals may be reluctant to disseminate genetic risk information. Rationally motivated individuals were better informed than emotionally motivated individuals. It is suggested that a leaflet is added to the invitation letter to enhance informed decision-making about genetic testing.

Characteristics of users of online personalized genomic risk assessments: implications for physician-patient interactions.

PubMed

McBride, Colleen M; Alford, Sharon Hensley; Reid, Robert J; Larson, Eric B; Baxevanis, Andreas D; Brody, Lawrence C

2009-08-01

To evaluate what psychological and behavioral factors predict who is likely to seek SNP-based genetic tests for multiple common health conditions where feedback can be used to motivate primary prevention. Adults aged 25-40 years who were enrolled in a large managed care organization were surveyed. Those eligible could log on to a secure study Web site to review information about the risks and benefits of a SNP-based genetic test and request free testing. Two primary outcomes are addressed: accessing the Web (yes or no) and deciding to be tested (completed a blood draw at the clinic) Those considering genetic susceptibility testing did not hold genetically deterministic beliefs (0.42 on scale of 0 [behavior] to 1 [genetic]) but believed genetic information to be valuable and were confident they could understand such information. Individuals who believed it important to learn about genetics (odds ratio = 1.28), were confident they could understand genetics (odds ratio = 1.26), and reported the most health habits to change (odds ratio = 1.39) were most likely to get tested. Individuals who present to health care providers with online genetics information may be among the most motivated to take steps toward healthier lifestyles. These motives might be leveraged by health care providers to promote positive health outcomes.

Integrating environmental and genetic effects to predict responses of tree populations to climate.

PubMed

Wang, Tongli; O'Neill, Gregory A; Aitken, Sally N

2010-01-01

Climate is a major environmental factor affecting the phenotype of trees and is also a critical agent of natural selection that has molded among-population genetic variation. Population response functions describe the environmental effect of planting site climates on the performance of a single population, whereas transfer functions describe among-population genetic variation molded by natural selection for climate. Although these approaches are widely used to predict the responses of trees to climate change, both have limitations. We present a novel approach that integrates both genetic and environmental effects into a single "universal response function" (URF) to better predict the influence of climate on phenotypes. Using a large lodgepole pine (Pinus contorta Dougl. ex Loud.) field transplant experiment composed of 140 populations planted on 62 sites to demonstrate the methodology, we show that the URF makes full use of data from provenance trials to: (1) improve predictions of climate change impacts on phenotypes; (2) reduce the size and cost of future provenance trials without compromising predictive power; (3) more fully exploit existing, less comprehensive provenance tests; (4) quantify and compare environmental and genetic effects of climate on population performance; and (5) predict the performance of any population growing in any climate. Finally, we discuss how the last attribute allows the URF to be used as a mechanistic model to predict population and species ranges for the future and to guide assisted migration of seed for reforestation, restoration, or afforestation and genetic conservation in a changing climate.

Clinical worthlessness of genetic prediction of common forms of diabetes mellitus and related chronic complications: A position statement of the Italian Society of Diabetology.

PubMed

Buzzetti, R; Prudente, S; Copetti, M; Dauriz, M; Zampetti, S; Garofolo, M; Penno, G; Trischitta, V

2017-02-01

We are currently facing several attempts aimed at marketing genetic data for predicting multifactorial diseases, among which diabetes mellitus is one of the more prevalent. The present document primarily aims at providing to practicing physicians a summary of available data regarding the role of genetic information in predicting diabetes and its chronic complications. Firstly, general information about characteristics and performance of risk prediction tools will be presented in order to help clinicians to get acquainted with basic methodological information related to the subject at issue. Then, as far as type 1 diabetes is concerned, available data indicate that genetic information and counseling may be useful only in families with many affected individuals. However, since no disease prevention is possible, the utility of predicting this form of diabetes is at question. In the case of type 2 diabetes, available data really question the utility of adding genetic information on top of well performing, easy available and inexpensive non-genetic markers. Finally, the possibility of using the few available genetic data on diabetic complications for improving our ability to predict them will also be presented and discussed. For cardiovascular complication, the addition of genetic information to models based on clinical features does not translate in a substantial improvement in risk discrimination. For all other diabetic complications genetic information are currently very poor and cannot, therefore, be used for improving risk stratification. In all, nowadays the use of genetic testing for predicting diabetes and its chronic complications is definitively of little value in clinical practice. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

[Genetic predisposition to breast and ovarian cancer: importance of test results].

PubMed

Julian-Reynier, Claire

2011-01-01

Oncogenetic consultations and predictive BRCA1/2 testing are intertwined processes and the specific impact of these genetic tests if performed alone through direct-to-consumer offers remains unknown. Noteworthy, the expectations of patients vary with their own status, whether they are affected or not by breast cancer at the time genetic testing is performed. The prescription of genetic tests for BCRA mutations has doubled in France between 2003 and 2009. There is a consensus on the fact that genetic results disclosure led to a significant increase in the knowledge and understanding that the patients have of the genetic risk and also changed the medical follow-up of these patients. Evaluating the psychological burden of tests disclosure did not reveal any major distress in patients who are followed by high-quality multidisciplinary teams. Longitudinal cohorts studies have now evaluated the perception and behaviour of these patients, and observed sociodemographic as well as geographic and psychosocial differences both in the acceptation of prophylactic strategies such as surgery, and time to surgery. © 2011 médecine/sciences - Inserm / SRMS.

Modern Advances in Genetic Testing: Ethical Challenges and Training Implications for Current and Future Psychologists

PubMed Central

Richmond-Rakerd, Leah S.

2014-01-01

The ethical implications for psychological practice of genetic testing are largely unexplored. Predictive testing can have a significant impact on health and well-being, and increasing numbers of individuals with knowledge of their risk for various disorders are likely to present for psychotherapy. In addition, more people will struggle with the decision of whether to obtain information regarding their genetic material. Psychologists will need to have the appropriate knowledge and clinical skills to effectively counsel this population. This article highlights the relevant ethical issues surrounding psychological treatment of individuals pursuing or considering undergoing genetic testing. These issues are extended to psychologists working in research, education, and policy domains. Recommendations for graduate training programs to facilitate current and future practitioner competence are also discussed. PMID:24707160

23andMe: a new two-sided data-banking market model.

PubMed

Stoeklé, Henri-Corto; Mamzer-Bruneel, Marie-France; Vogt, Guillaume; Hervé, Christian

2016-03-31

Since 2006, the genetic testing company 23andMe has collected biological samples, self-reported information, and consent documents for biobanking and research from more than 1,000,000 individuals (90% participating in research), through a direct-to-consumer (DTC) online genetic-testing service providing a genetic ancestry report and a genetic health report. However, on November 22, 2013, the Food and Drug Administration (FDA) halted the sale of genetic health testing, on the grounds that 23andMe was not acting in accordance with federal law, by selling tests of undemonstrated reliability as predictive tests for medical risk factors. Consumers could still obtain the genetic ancestry report, but they no longer had access to the genetic health report in the United States (US). However, this did not prevent the company from continuing its health research, with previously obtained and future samples, provided that consent had been obtained from the consumers concerned, or with health reports for individuals from other countries. Furthermore, 23andMe was granted FDA authorization on February 19, 2015, first to provide reports about Bloom syndrome carrier status, and, more recently, to provide consumers with "carrier status" information for 35 genes known (with high levels of confidence) to cause disease. In this Debate, we highlight the likelihood that the primary objective of the company was probably two-fold: promoting itself within the market for predictive testing for human genetic diseases and ancestry at a low cost to consumers, and establishing a high-value database/biobank for research (one of the largest biobanks of human deoxyribonucleic acid (DNA) and personal information). By dint of this marketing approach, a two-sided market has been established between the consumer and the research laboratories, involving the establishment of a database/DNA biobank for scientific and financial gain. We describe here the profound ethical issues raised by this setup.

Optimality models in the age of experimental evolution and genomics.

PubMed

Bull, J J; Wang, I-N

2010-09-01

Optimality models have been used to predict evolution of many properties of organisms. They typically neglect genetic details, whether by necessity or design. This omission is a common source of criticism, and although this limitation of optimality is widely acknowledged, it has mostly been defended rather than evaluated for its impact. Experimental adaptation of model organisms provides a new arena for testing optimality models and for simultaneously integrating genetics. First, an experimental context with a well-researched organism allows dissection of the evolutionary process to identify causes of model failure--whether the model is wrong about genetics or selection. Second, optimality models provide a meaningful context for the process and mechanics of evolution, and thus may be used to elicit realistic genetic bases of adaptation--an especially useful augmentation to well-researched genetic systems. A few studies of microbes have begun to pioneer this new direction. Incompatibility between the assumed and actual genetics has been demonstrated to be the cause of model failure in some cases. More interestingly, evolution at the phenotypic level has sometimes matched prediction even though the adaptive mutations defy mechanisms established by decades of classic genetic studies. Integration of experimental evolutionary tests with genetics heralds a new wave for optimality models and their extensions that does not merely emphasize the forces driving evolution.

Ethical issues in pediatric genetic testing and screening.

PubMed

Botkin, Jeffrey R

2016-12-01

Developments in genetic test technologies enable a detailed analysis of the genomes of individuals across the range of human development from embryos to adults with increased precision and lower cost. These powerful technologies raise a number of ethical issues in pediatrics, primarily because of the frequent lack of clinical utility of genetic information, the generation of secondary results and questions over the proper scope of parental authority for testing. Several professional organizations in the fields of genetics and pediatrics have published new guidance on the ethical, legal, and policy issues relevant to genetic testing in children. The roles of predictive testing for adult-onset conditions, the management of secondary findings and the role of informed consent for newborn screening remain controversial. However, research and experience are not demonstrating serious adverse psychosocial impacts from genetic testing and screening in children. The use of these technologies is expanding with the notion that the personal utility of test results, rather than clinical utility, may be sufficient to justify testing. The use of microarray and genome sequencing technologies is expanding in the care of children. More deference to parental decision-making is evolving in contexts wherein information and counseling can be made readily available.

Genetic variants linked to education predict longevity

PubMed Central

Marioni, Riccardo E.; Ritchie, Stuart J.; Joshi, Peter K.; Hagenaars, Saskia P.; Fischer, Krista; Adams, Mark J.; Hill, W. David; Davies, Gail; Nagy, Reka; Amador, Carmen; Läll, Kristi; Metspalu, Andres; Liewald, David C.; Wilson, James F.; Hayward, Caroline; Esko, Tõnu; Porteous, David J.; Gale, Catharine R.; Deary, Ian J.

2016-01-01

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members’ polygenic profile score for education to predict their parents’ longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼2.4% lower risk for fathers (total ndeaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. PMID:27799538

Genetic variants linked to education predict longevity.

PubMed

Marioni, Riccardo E; Ritchie, Stuart J; Joshi, Peter K; Hagenaars, Saskia P; Okbay, Aysu; Fischer, Krista; Adams, Mark J; Hill, W David; Davies, Gail; Nagy, Reka; Amador, Carmen; Läll, Kristi; Metspalu, Andres; Liewald, David C; Campbell, Archie; Wilson, James F; Hayward, Caroline; Esko, Tõnu; Porteous, David J; Gale, Catharine R; Deary, Ian J

2016-11-22

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.

Heritabilities of measured and mid-infrared predicted milk fat globule size, milk fat and protein percentages, and their genetic correlations.

PubMed

Fleming, A; Schenkel, F S; Koeck, A; Malchiodi, F; Ali, R A; Corredig, M; Mallard, B; Sargolzaei, M; Miglior, F

2017-05-01

The objective of this study was to estimate the heritability of milk fat globule (MFG) size and mid-infrared (MIR) predicted MFG size in Holstein cattle. The genetic correlations between measured and predicted MFG size with milk fat and protein percentage were also investigated. Average MFG size was measured in 1,583 milk samples taken from 254 Holstein cows from 29 herds across Canada. Size was expressed as volume moment mean (D[4,3]) and surface moment mean (D[3,2]). Analyzed milk samples also had average MFG size predicted from their MIR spectral records. Fat and protein percentages were obtained for all test-day milk samples in the cow's lactation. Univariate and bivariate repeatability animal models were used to estimate heritability and genetic correlations. Moderate heritabilities of 0.364 and 0.466 were found for D[4,3] and D[3,2], respectively, and a strong genetic correlation was found between the 2 traits (0.98). The heritabilities for the MIR-predicted MFG size were lower than those estimated for the measured MFG size at 0.300 for predicted D[4,3] and 0.239 for predicted D[3,2]. The genetic correlation between measured and predicted D[4,3] was 0.685; the correlation was slightly higher between measured and predicted D[3,2] at 0.764, likely due to the better prediction accuracy of D[3,2]. Milk fat percentage had moderate genetic correlations with both D[4,3] and D[3,2] (0.538 and 0.681, respectively). The genetic correlation between predicted MFG size and fat percentage was much stronger (greater than 0.97 for both predicted D[4,3] and D[3,2]). The stronger correlation suggests a limitation for the use of the predicted values of MFG size as indicator traits for true average MFG size in milk in selection programs. Larger samples sizes are required to provide better evidence of the estimated genetic parameters. A genetic component appears to exist for the average MFG size in bovine milk, and the variation could be exploited in selection programs. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Which lessons can we learn from the European Union legal framework of medicines for the regulation of direct-to-consumer genetic tests?

PubMed

van Hellemondt, Rachèl; Hendriks, Aart; Breuning, Martijn

2012-01-01

The legal framework of the European Union (EU) for regulating access to and supply of direct-to-consumer (DTC) genetic tests is very liberal compared to the legal and regulatory framework for (internet) medicines. Nevertheless, both health related products can cause equally serious damage to the well being of individuals. In this contribution we examine whether the legal framework of the EU for the safety and responsible use of (internet) medicines could be an example for regulating access to and supply of DTC genetic tests. The EU laws governing medicines can, notwithstanding their shortcomings, serve as an example for (central) authorising the marketing of DTC genetic tests on the internal market in accordance with strict criteria regarding predictive value and clinical usefulness. Furthermore, a legal framework controlling DTC genetic tests also should introduce system supervision as well as quality criteria with respect to the information to be provided to consumers in order to enhance health protection. However, DTC genetic tests purchased through online ordering are difficult to supervise by any agency. Adequately protecting individuals against questionable testing kits calls for international vigilance and comprehensive measures by the international community. For Europe, it is important to rank the regulation of DTC genetic tests on the European regulatory agenda.

Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.

PubMed

McNally, Elizabeth M; Mestroni, Luisa

2017-09-15

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management. © 2017 American Heart Association, Inc.

Predictive potential of IL-28B genetic testing for interferon based hepatitis C virus therapy in Pakistan: Current scenario and future perspective.

PubMed

Afzal, Muhammad Sohail

2016-09-18

In Pakistan which ranked second in terms of hepatitis C virus (HCV) infection, it is highly needed to have an established diagnostic test for antiviral therapy response prediction. Interleukin 28B (IL-28B) genetic testing is widely used throughout the world for interferon based therapy prediction for HCV patients and is quite helpful not only for health care workers but also for the patients. There is a strong relationship between single nucleotide polymorphisms at or near the IL-28B gene and the sustained virological response with pegylated interferon plus ribavirin treatment for chronic hepatitis C. Pakistan is a resource limited country, with very low per capita income and there is no proper social security (health insurance) system. The allocated health budget by the government is very low and is used on other health emergencies like polio virus and dengue virus infection. Therefore it is proposed that there should be a well established diagnostic test on the basis of IL-28B which can predict the antiviral therapy response to strengthen health care set-up of Pakistan. This test once established will help in better management of HCV infected patients.

The impact of receiving predictive genetic information about Lynch syndrome on individual colonoscopy and smoking behaviors

PubMed Central

Kim, Joanne Soo-Min; Coyte, Peter C.; Cotterchio, Michelle; Keogh, Louise A.; Flander, Louisa B.; Gaff, Clara; Laporte, Audrey

2016-01-01

Background This study investigated whether receiving the results of predictive genetic testing for Lynch syndrome—indicating the presence or absence of an inherited predisposition to various cancers, including colorectal cancer—was associated with change in individual colonoscopy and smoking behaviours, which could prevent colorectal cancer. Methods The study population included individuals with no previous diagnosis of colorectal cancer, whose families had already-identified deleterious mutations in the mismatch repair or EPCAM genes. Hypotheses were generated from a simple health economics model and tested against individual-level panel data from the Australasian Colorectal Cancer Family Registry. Results The empirical analysis revealed evidence consistent with some of the hypotheses, with a higher likelihood of undergoing colonoscopy in those who discovered their genetic predisposition to colorectal cancer and a lower likelihood of quitting smoking in those who discovered their lack thereof. Conclusion Predictive genetic information about Lynch syndrome was associated with change in individual colonoscopy and smoking behaviours but not necessarily in ways to improve population health. Impact The study findings suggest that the impact of personalized medicine on disease prevention is intricate, warranting further analyses to determine the net benefits and costs. PMID:27528600

Genetic and life-history consequences of extreme climate events.

PubMed

Vincenzi, Simone; Mangel, Marc; Jesensek, Dusan; Garza, John Carlos; Crivelli, Alain J

2017-02-08

Climate change is predicted to increase the frequency and intensity of extreme climate events. Tests on empirical data of theory-based predictions on the consequences of extreme climate events are thus necessary to understand the adaptive potential of species and the overarching risks associated with all aspects of climate change. We tested predictions on the genetic and life-history consequences of extreme climate events in two populations of marble trout Salmo marmoratus that have experienced severe demographic bottlenecks due to flash floods. We combined long-term field and genotyping data with pedigree reconstruction in a theory-based framework. Our results show that after flash floods, reproduction occurred at a younger age in one population. In both populations, we found the highest reproductive variance in the first cohort born after the floods due to a combination of fewer parents and higher early survival of offspring. A small number of parents allowed for demographic recovery after the floods, but the genetic bottleneck further reduced genetic diversity in both populations. Our results also elucidate some of the mechanisms responsible for a greater prevalence of faster life histories after the extreme event. © 2017 The Author(s).

Attitudes toward prenatal genetic testing for Treacher Collins syndrome among affected individuals and families.

PubMed

Wu, Rebecca L; Lawson, Cathleen S; Jabs, Ethylin Wang; Sanderson, Saskia C

2012-07-01

Treacher Collins syndrome (TCS) is a craniofacial syndrome that is both phenotypically variable and heterogeneous, caused by mutations in the TCOF1, POLR1C, and POLR1D genes. We examined attitudes towards TCS prenatal genetic testing among affected families using a telephone questionnaire. Participants were 31 affected adults and relatives recruited primarily through families cared for in the mid-Atlantic region. Nineteen participants (65%) reported that they would take a TCS prenatal genetic test which could not predict degree of disease severity. Interest in TCS genetic testing was associated with higher income, higher concern about having a child with TCS, lower religiosity, lower concern about genetic testing procedures, and having a sporadic rather than familial mutation. Over half reported that their decision to have TCS genetic testing would be influenced a great deal by their desire to relieve anxiety and attitudes toward abortion. Ten participants (32%) reported that they would be likely to end the pregnancy upon receiving a positive test result; this was lower amongst TCS affected individuals and higher amongst participants with children with TCS. Genetics healthcare providers need to be aware of affected individuals' and families' attitudes and interest in prenatal genetic testing for TCS, and the possible implications for other craniofacial disorders, so that patients' information needs can be met. Copyright © 2012 Wiley Periodicals, Inc.

Family conflict interacts with genetic liability in predicting childhood and adolescent depression.

PubMed

Rice, Frances; Harold, Gordon T; Shelton, Katherine H; Thapar, Anita

2006-07-01

To test for gene-environment interaction with depressive symptoms and family conflict. Specifically, to first examine whether the influence of family conflict in predicting depressive symptoms is increased in individuals at genetic risk of depression. Second, to test whether the genetic component of variance in depressive symptoms increases as levels of family conflict increase. A longitudinal twin design was used. Children ages 5 to 16 were reassessed approximately 3 years later to test whether the influence of family conflict in predicting depressive symptoms varied according to genetic liability. The conflict subscale of the Family Environment Scale was used to assess family conflict and the Mood and Feelings Questionnaire was used to assess depressive symptoms. The response rate to the questionnaire at time 1 was 73% and 65% at time 2. Controlling for initial symptoms levels (i.e., internalizing at time 1), primary analyses were conducted using ordinary least-squares multiple regression. Structural equation models, using raw score maximum likelihood estimation, were also fit to the data for the purpose of model fit comparison. Results suggested significant gene-environment interaction specifically with depressive symptoms and family conflict. Genetic factors were of greater importance in the etiology of depressive symptoms where levels of family conflict were high. The effects of family conflict on depressive symptoms were greater in children and adolescents at genetic risk of depression. The present results suggest that children with a family history of depression may be at an increased risk of developing depressive symptoms in response to family conflict. Intervention programs that incorporate one or more family systems may be of benefit in alleviating the adverse effect of negative family factors on children.

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.

PubMed

Rohde, Palle Duun; Demontis, Ditte; Cuyabano, Beatriz Castro Dias; Børglum, Anders D; Sørensen, Peter

2016-08-01

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies. Copyright © 2016 by the Genetics Society of America.

Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

PubMed

Rosenthal, E T; Bowles, K R; Pruss, D; van Kan, A; Vail, P J; McElroy, H; Wenstrup, R J

2015-12-01

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified. © 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The evolution of polyandry: patterns of genotypic variation in female mating frequency, male fertilization success and a test of the sexy-sperm hypothesis.

PubMed

Simmons, L W

2003-07-01

The sexy-sperm hypothesis predicts that females obtain indirect benefits for their offspring via polyandy, in the form of increased fertilization success for their sons. I use a quantitative genetic approach to test the sexy-sperm hypothesis using the field cricket Teleogryllus oceanicus. Previous studies of this species have shown considerable phenotypic variation in fertilization success when two or more males compete. There were high broad-sense heritabilities for both paternity and polyandry. Patterns of genotypic variance were consistent with X-linked inheritance and/or maternal effects on these traits. The genetic architecture therefore precludes the evolution of polyandry via a sexy-sperm process. Thus the positive genetic correlation between paternity in sons and polyandry in daughters predicted by the sexy-sperm hypothesis was absent. There was significant heritable variation in the investment by females in ovaries and by males in the accessory gland. Surprisingly there was a very strong genetic correlation between these two traits. The significance of this genetic correlation for the coevolution of male seminal products and polyandry is discussed.

Investigating genetic discrimination in Australia: a large-scale survey of clinical genetics clients.

PubMed

Taylor, S; Treloar, S; Barlow-Stewart, K; Stranger, M; Otlowski, M

2008-07-01

We report first results from the Australian Genetic Discrimination Project of clinical genetics services clients' perceptions and experiences regarding alleged differential treatment associated with having genetic information. Adults (n = 2667) who had presented from 1998 to 2003 regarding predictive or presymptomatic testing for designated mature-onset conditions were surveyed; 951/1185 respondents met inclusion criteria for current asymptomatic status. Neurological conditions and familial cancers were primary relevant conditions for 87% of asymptomatic respondents. Specific incidents of alleged negative treatment, reported by 10% (n = 93) of respondents, occurred in life insurance (42%), employment (5%), family (22%), social (11%) and health (20%) domains. Respondents where neuro-degenerative conditions were relevant were more likely overall to report incidents and significantly more likely to report incidents in the social domain. Most incidents in the post-test period occurred in the first year after testing. Only 15% of respondents knew where to complain officially if treated negatively because of genetics issues. Recommendations include the need for increased community and clinical education regarding genetic discrimination, for extended clinical genetics sector engagement and for co-ordinated monitoring, research and policy development at national levels in order for the full benefits of genetic testing technology to be realised.

Insurance and genetic testing: where are we now?

PubMed Central

Ostrer, H; Allen, W; Crandall, L A; Moseley, R E; Dewar, M A; Nye, D; McCrary, S V

1993-01-01

Basic research will spur development of genetic tests that are capable of presymptomatic prediction of disease, disability, and premature death in presently asymptomatic individuals. Concerns have been expressed about potential harms related to the use of genetic test results, especially loss of confidentiality, eugenics, and discrimination. Existing laws and administrative policies may not be sufficient to assure that genetic information is used fairly. To provide factual information and conceptual principles upon which sound social policy can be based, the Human Genome Initiative established an Ethical, Legal, and Social Issues Program. Among the first areas to be identified as a priority for study was insurance. This paper provides a review of life, health, and disability insurance systems, including basic principles, risk classification, and market and regulatory issues, and examines the potential impact of genetic information on the insurance industry. PMID:8447322

Geneticization of deviant behavior and consequences for stigma: the case of mental illness.

PubMed

Phelan, Jo C

2005-12-01

One likely consequence of the genetics revolution is an increased tendency to understand human behavior in genetic terms. How might this "geneticization" affect stigma? Attribution theory predicts a reduction in stigma via reduced blame, anger, and punishment and increased sympathy and help. According to "genetic essentialist" thinking, genes are the basis of human identity and strongly deterministic of behavior. If such ideas are commonly accepted, geneticization should exacerbate stigma by increasing perceptions of differentness, persistence, seriousness, and transmissibility, which in turn should increase social distance and reproductive restrictiveness. I test these predictions using the case of mental illness and a vignette experiment embedded in a nationally representative survey. There was little support for attribution theory predictions. Consistent with genetic essentialism, genetic attributions increased the perceived seriousness and persistence of the mental illness and the belief that siblings and children would develop the same problem. Genetic attribution did not affect reproductive restrictiveness or social distance from the ill person but did increase social distance from the person's sibling, particularly regarding intimate forms of contact involving dating, marriage, and having children.

Ethical issues in ocular genetics.

PubMed

Mezer, Eedy; Wygnanski-Jaffe, Tamara

2009-09-01

To review some of the major issues in ophthalmic genetics ethics: predictive testing, prenatal testing and abortion, gene therapy, confidentiality, payment for genetic testing, the duty to recontact patients and convey new information. Patients and families may perceive benefits even though genetic testing may be associated with adverse psychosocial outcomes. Most patients were in favor of prenatal diagnosis but opposed abortion. Patient selection as candidates for gene therapy should be based on the different clinical characteristics of each hereditary disease. The balance between the right of the patient for confidentiality and the best interest of family members or society is an ethical challenge. Most insurance companies will pay for genetic testing if the condition is hereditary. The duty to recontact patients when new medical information becomes available is still ethically controversial. The field of ocular genetics is ever growing involving complex medical, technical, financial and social issues. As a result, ethical issues are expected to become more common. Properly prepared medical professionals as well as unique counseling for participants and families may enable improved decision-making taking into consideration the needs of each individual.

Final Report: The DNA Files: Unraveling the mysteries of genetics, January 1, 1998-March 31, 1999

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scott, Bari

1999-05-01

The DNA Files is an award-winning radio documentary series on genetics created by SoundVision Productions. The DNA Files was hosted by John Hockenberry and was presented in documentary and discussion format. The programs covered a range of topics from prenatal and predictive gene testing, gene therapy, and commercialization of genetic information to new evolutionary genetic evidence, transgenic vegetables and use of DNA in forensics.

Genetic testing and sports medicine ethics.

PubMed

McNamee, Michael John; Müller, Arno; van Hilvoorde, Ivo; Holm, Søren

2009-01-01

Sports medicine ethics is neither a well established branch of sports medicine nor of medical ethics. It is therefore important to raise to more general awareness some of the significant ethical implications of sports medicine practices. The field of genetics in sports is likewise in its infancy and raises significant ethical concerns. It is not yet clear how genetics will alter our understanding of human potential and performance in sports. While a number of professional medical bodies accept genetic interventions of a therapeutic nature, we argue that the use of genetic technologies to predict sports potential may well breach both the European bioethics convention and North American anti-discrimination legislation, which are designed to support important ethical ideals and the ongoing commitment of the physician to the welfare of their patient. We highlight further ethical problems associated with confidentiality and consent that may arise in genetic testing as opposed to more conventional methods of testing in sports medicine. We conclude that genetic testing in sport that is not strictly limited to the protection of the athlete against harm, should be viewed in a very sceptical light by sports medicine professionals.

Genetics and crime: Integrating new genomic discoveries into psychological research about antisocial behavior

PubMed Central

Wertz, J.; Caspi, A.; Belsky, D. W.; Beckley, A. L.; Arseneault, L.; Barnes, J. C.; Corcoran, D. L.; Hogan, S.; Houts, R. M.; Morgan, N.; Odgers, C. L.; Prinz, J. A.; Sugden, K.; Williams, B. S.; Poulton, R.; Moffitt, T. E.

2018-01-01

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and E-Risk birth cohorts of individuals growing up 20 years and 20,000 kilometres apart, education polygenic scores predicted risk of a criminal record, with modest effects. Polygenic risk manifested during primary schooling, in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and predicted a life-course persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature/nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest the hypothesis that improving school experiences might prevent genetic influences on crime from unfolding. PMID:29513605

Prediction of early weight gain during psychotropic treatment using a combinatorial model with clinical and genetic markers.

PubMed

Vandenberghe, Frederik; Saigí-Morgui, Núria; Delacrétaz, Aurélie; Quteineh, Lina; Crettol, Séverine; Ansermot, Nicolas; Gholam-Rezaee, Mehdi; von Gunten, Armin; Conus, Philippe; Eap, Chin B

2016-12-01

Psychotropic drugs can induce significant (>5%) weight gain (WG) already after 1 month of treatment, which is a good predictor for major WG at 3 and 12 months. The large interindividual variability of drug-induced WG can be explained in part by genetic and clinical factors. The aim of this study was to determine whether extensive analysis of genes, in addition to clinical factors, can improve prediction of patients at risk for more than 5% WG at 1 month of treatment. Data were obtained from a 1-year naturalistic longitudinal study, with weight monitoring during weight-inducing psychotropic treatment. A total of 248 Caucasian psychiatric patients, with at least baseline and 1-month weight measures, and with compliance ascertained were included. Results were tested for replication in a second cohort including 32 patients. Age and baseline BMI were associated significantly with strong WG. The area under the curve (AUC) of the final model including genetic (18 genes) and clinical variables was significantly greater than that of the model including clinical variables only (AUCfinal: 0.92, AUCclinical: 0.75, P<0.0001). Predicted accuracy increased by 17% with genetic markers (Accuracyfinal: 87%), indicating that six patients must be genotyped to avoid one misclassified patient. The validity of the final model was confirmed in a replication cohort. Patients predicted before treatment as having more than 5% WG after 1 month of treatment had 4.4% more WG over 1 year than patients predicted to have up to 5% WG (P≤0.0001). These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG.

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

PubMed Central

Plon, Sharon E.; Eccles, Diana M.; Easton, Douglas; Foulkes, William D.; Genuardi, Maurizio; Greenblatt, Marc S.; Hogervorst, Frans B.L.; Hoogerbrugge, Nicoline; Spurdle, Amanda B.; Tavtigian, Sean

2011-01-01

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology and propose a standardized classification system for application to sequence based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. PMID:18951446

Mid-infrared spectroscopy predictions as indicator traits in breeding programs for enhanced coagulation properties of milk.

PubMed

Cecchinato, A; De Marchi, M; Gallo, L; Bittante, G; Carnier, P

2009-10-01

The aims of this study were to investigate variation of milk coagulation property (MCP) measures and their predictions obtained by mid-infrared spectroscopy (MIR), to investigate the genetic relationship between measures of MCP and MIR predictions, and to estimate the expected response from a breeding program focusing on the enhancement of MCP using MIR predictions as indicator traits. Individual milk samples were collected from 1,200 Brown Swiss cows (progeny of 50 artificial insemination sires) reared in 30 herds located in northern Italy. Rennet coagulation time (RCT, min) and curd firmness (a(30), mm) were measured using a computerized renneting meter. The MIR data were recorded over the spectral range of 4,000 to 900 cm(-1). Prediction models for RCT and a(30) based on MIR spectra were developed using partial least squares regression. A cross-validation procedure was carried out. The procedure involved the partition of available data into 2 subsets: a calibration subset and a test subset. The calibration subset was used to develop a calibration equation able to predict individual MCP phenotypes using MIR spectra. The test subset was used to validate the calibration equation and to estimate heritabilities and genetic correlations for measured MCP and their predictions obtained from MIR spectra and the calibration equation. Point estimates of heritability ranged from 0.30 to 0.34 and from 0.22 to 0.24 for RCT and a(30), respectively. Heritability estimates for MCP predictions were larger than those obtained for measured MCP. Estimated genetic correlations between measures and predictions of RCT were very high and ranged from 0.91 to 0.96. Estimates of the genetic correlation between measures and predictions of a(30) were large and ranged from 0.71 to 0.87. Predictions of MCP provided by MIR techniques can be proposed as indicator traits for the genetic enhancement of MCP. The expected response of RCT and a(30) ensured by the selection using MIR predictions as indicator traits was equal to or slightly less than the response achievable through a single measurement of these traits. Breeding strategies for the enhancement of MCP based on MIR predictions as indicator traits could be easily and immediately implemented for dairy cattle populations where routine acquisition of spectra from individual milk samples is already performed.

The perceived and predicted implications of psychiatric genetic knowledge among persons with multiple cases of depression in the family.

PubMed

Laegsgaard, M M; Stamp, A S; Hall, E O C; Mors, O

2010-12-01

Psychiatric genetic research raises hope regarding better treatment and prevention, but also regarding a possible de-stigmatizing effect of attributing mental illness to genetics. This study explores i) the impact on family relations of participating in a genetic study; ii) the impact of biogenetic attributions on perceptions of depression and stigma and iii) the perceived benefits and concerns regarding psychiatric genetic testing. Focus groups were conducted with 17 participants suffering from depression, with multiple cases of depression in the family, and previously participating in a genetic study. Participating in a genetic study caused more openness about depression in most families. A biogenetic explanation of depression was perceived as having the potential of diminishing self stigma. Testing of self and children was widely accepted, whereas prenatal testing raised concern. Persons suffering from depression may benefit from endorsing a biogenetic explanation, especially in relation to self-understanding and self-stigma. © 2010 John Wiley & Sons A/S.

The science of tobacco addiction and cessation.

PubMed

2014-01-01

Over the past decade, researchers have found genetic variations that affect how nicotine, the main addictive component of tobacco, interacts with cells in the brain and how fast the body metabolizes it. Carrying a high-risk variant predicts a person's ability to snuff out their cigarettes for good. Genetic testing could help predict which smokers might benefit from nicotine replacement therapy or other prescription medications, much like sequencing of malignant tumors can point to the most effective cancer treatment.

Impact of genetic risk information and type of disease on perceived risk, anticipated affect, and expected consequences of genetic tests.

PubMed

Cameron, Linda D; Sherman, Kerry A; Marteau, Theresa M; Brown, Paul M

2009-05-01

Genetic tests vary in their prediction of disease occurrence, with some mutations conferring relatively low risk and others indicating near certainty. The authors assessed how increments in absolute risk of disease influence risk perceptions, interest, and expected consequences of genetic tests for diseases of varying severity. Adults (N = 752), recruited from New Zealand, Australia, and the United Kingdom for an online analogue study, were randomly assigned to receive information about a test of genetic risk for diabetes, heart disease, colon cancer, or lung cancer. The lifetime risk varied across conditions by 10% increments, from 20% to 100%. Participants completed measures of perceived likelihood of disease for individuals with mutations, risk-related affect, interest, and testing consequences. Analyses revealed two increment clusters yielding differences in likelihood perceptions: A "moderate-risk" cluster (20%-70%), and a "high-risk" cluster (80%-100%). Risk increment influenced anticipated worry, feelings of risk, testing-induced distress, and family obligations, with nonlinear patterns including disproportionately high responses for the 50% increment. Risk increment did not alter testing interest or perceived benefits. These patterns of effects held across the four diseases. Magnitude of risk from genetic testing has a nonlinear influence on risk-related appraisals and affect but is unrelated to test interest.

The alignment between phenotypic plasticity, the major axis of genetic variation and the response to selection.

PubMed

Lind, Martin I; Yarlett, Kylie; Reger, Julia; Carter, Mauricio J; Beckerman, Andrew P

2015-10-07

Phenotypic plasticity is the ability of a genotype to produce more than one phenotype in order to match the environment. Recent theory proposes that the major axis of genetic variation in a phenotypically plastic population can align with the direction of selection. Therefore, theory predicts that plasticity directly aids adaptation by increasing genetic variation in the direction favoured by selection and reflected in plasticity. We evaluated this theory in the freshwater crustacean Daphnia pulex, facing predation risk from two contrasting size-selective predators. We estimated plasticity in several life-history traits, the G matrix of these traits, the selection gradients on reproduction and survival, and the predicted responses to selection. Using these data, we tested whether the genetic lines of least resistance and the predicted response to selection aligned with plasticity. We found predator environment-specific G matrices, but shared genetic architecture across environments resulted in more constraint in the G matrix than in the plasticity of the traits, sometimes preventing alignment of the two. However, as the importance of survival selection increased, the difference between environments in their predicted response to selection increased and resulted in closer alignment between the plasticity and the predicted selection response. Therefore, plasticity may indeed aid adaptation to new environments. © 2015 The Authors.

Laboratory evolution of the migratory polymorphism in the sand cricket: combining physiology with quantitative genetics.

PubMed

Roff, Derek A; Fairbairn, Daphne J

2007-01-01

Predicting evolutionary change is the central goal of evolutionary biology because it is the primary means by which we can test evolutionary hypotheses. In this article, we analyze the pattern of evolutionary change in a laboratory population of the wing-dimorphic sand cricket Gryllus firmus resulting from relaxation of selection favoring the migratory (long-winged) morph. Based on a well-characterized trade-off between fecundity and flight capability, we predict that evolution in the laboratory environment should result in a reduction in the proportion of long-winged morphs. We also predict increased fecundity and reduced functionality and weight of the major flight muscles in long-winged females but little change in short-winged (flightless) females. Based on quantitative genetic theory, we predict that the regression equation describing the trade-off between ovary weight and weight of the major flight muscles will show a change in its intercept but not in its slope. Comparisons across generations verify all of these predictions. Further, using values of genetic parameters estimated from previous studies, we show that a quantitative genetic simulation model can account for not only the qualitative changes but also the evolutionary trajectory. These results demonstrate the power of combining quantitative genetic and physiological approaches for understanding the evolution of complex traits.

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe.

PubMed

Hastings, Ros; de Wert, Guido; Fowler, Brian; Krawczak, Michael; Vermeulen, Eric; Bakker, Egbert; Borry, Pascal; Dondorp, Wybo; Nijsingh, Niels; Barton, David; Schmidtke, Jörg; van El, Carla G; Vermeesch, Joris; Stol, Yrrah; Carmen Howard, Heidi; Cornel, Martina C

2012-09-01

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research.

Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations

PubMed Central

Saigi-Morgui, Núria; Quteineh, Lina; Bochud, Pierre-Yves; Crettol, Severine; Kutalik, Zoltán; Wojtowicz, Agnieszka; Bibert, Stéphanie; Beckmann, Sonja; Mueller, Nicolas J; Binet, Isabelle; van Delden, Christian; Steiger, Jürg; Mohacsi, Paul; Stirnimann, Guido; Soccal, Paola M.; Pascual, Manuel; Eap, Chin B

2016-01-01

Background Polygenic obesity in Solid Organ Transplant (SOT) populations is considered a risk factor for the development of metabolic abnormalities and graft survival. Few studies to date have studied the genetics of weight gain in SOT recipients. We aimed to determine whether weighted genetic risk scores (w-GRS) integrating genetic polymorphisms from GWAS studies (SNP group#1 and SNP group#2) and from Candidate Gene studies (SNP group#3) influence BMI in SOT populations and if they predict ≥10% weight gain (WG) one year after transplantation. To do so, two samples (nA = 995, nB = 156) were obtained from naturalistic studies and three w-GRS were constructed and tested for association with BMI over time. Prediction of 10% WG at one year after transplantation was assessed with models containing genetic and clinical factors. Results w-GRS were associated with BMI in sample A and B combined (BMI increased by 0.14 and 0.11 units per additional risk allele in SNP group#1 and #2, respectively, p-values<0.008). w-GRS of SNP group#3 showed an effect of 0.01 kg/m2 per additional risk allele when combining sample A and B (p-value 0.04). Models with genetic factors performed better than models without in predicting 10% WG at one year after transplantation. Conclusions This is the first study in SOT evaluating extensively the association of w-GRS with BMI and the influence of clinical and genetic factors on 10% of WG one year after transplantation, showing the importance of integrating genetic factors in the final model. Genetics of obesity among SOT recipients remains an important issue and can contribute to treatment personalization and prediction of WG after transplantation. PMID:27788139

Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations.

PubMed

Saigi-Morgui, Núria; Quteineh, Lina; Bochud, Pierre-Yves; Crettol, Severine; Kutalik, Zoltán; Wojtowicz, Agnieszka; Bibert, Stéphanie; Beckmann, Sonja; Mueller, Nicolas J; Binet, Isabelle; van Delden, Christian; Steiger, Jürg; Mohacsi, Paul; Stirnimann, Guido; Soccal, Paola M; Pascual, Manuel; Eap, Chin B

2016-01-01

Polygenic obesity in Solid Organ Transplant (SOT) populations is considered a risk factor for the development of metabolic abnormalities and graft survival. Few studies to date have studied the genetics of weight gain in SOT recipients. We aimed to determine whether weighted genetic risk scores (w-GRS) integrating genetic polymorphisms from GWAS studies (SNP group#1 and SNP group#2) and from Candidate Gene studies (SNP group#3) influence BMI in SOT populations and if they predict ≥10% weight gain (WG) one year after transplantation. To do so, two samples (nA = 995, nB = 156) were obtained from naturalistic studies and three w-GRS were constructed and tested for association with BMI over time. Prediction of 10% WG at one year after transplantation was assessed with models containing genetic and clinical factors. w-GRS were associated with BMI in sample A and B combined (BMI increased by 0.14 and 0.11 units per additional risk allele in SNP group#1 and #2, respectively, p-values<0.008). w-GRS of SNP group#3 showed an effect of 0.01 kg/m2 per additional risk allele when combining sample A and B (p-value 0.04). Models with genetic factors performed better than models without in predicting 10% WG at one year after transplantation. This is the first study in SOT evaluating extensively the association of w-GRS with BMI and the influence of clinical and genetic factors on 10% of WG one year after transplantation, showing the importance of integrating genetic factors in the final model. Genetics of obesity among SOT recipients remains an important issue and can contribute to treatment personalization and prediction of WG after transplantation.

Predictive gene testing for Huntington disease and other neurodegenerative disorders.

PubMed

Wedderburn, S; Panegyres, P K; Andrew, S; Goldblatt, J; Liebeck, T; McGrath, F; Wiltshire, M; Pestell, C; Lee, J; Beilby, J

2013-12-01

Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty-eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre-implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

PubMed

Visscher, H; Ross, C J D; Rassekh, S R; Sandor, G S S; Caron, H N; van Dalen, E C; Kremer, L C; van der Pal, H J; Rogers, P C; Rieder, M J; Carleton, B C; Hayden, M R

2013-08-01

The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options. Copyright © 2013 Wiley Periodicals, Inc.

Privacy-preserving genomic testing in the clinic: a model using HIV treatment.

PubMed

McLaren, Paul J; Raisaro, Jean Louis; Aouri, Manel; Rotger, Margalida; Ayday, Erman; Bartha, István; Delgado, Maria B; Vallet, Yannick; Günthard, Huldrych F; Cavassini, Matthias; Furrer, Hansjakob; Doco-Lecompte, Thanh; Marzolini, Catia; Schmid, Patrick; Di Benedetto, Caroline; Decosterd, Laurent A; Fellay, Jacques; Hubaux, Jean-Pierre; Telenti, Amalio

2016-08-01

The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics. We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers. A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%. The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine.Genet Med 18 8, 814-822.

DEVELOPMENT OF AQUATIC MODELS FOR TESTING THE RELATIONSHIP BETWEEN GENETIC DIVERSITY AND POPULATION EXTINCTION RISK

EPA Science Inventory

The relationship between population adaptive potential and extinction risk in a changing environment is not well understood. Although the expectation is that genetic diversity is directly related to the capacity of populations to adapt, the statistical and predictive aspects of ...

Near infrared spectrometric technique for testing fruit quality: optimisation of regression models using genetic algorithms

NASA Astrophysics Data System (ADS)

Isingizwe Nturambirwe, J. Frédéric; Perold, Willem J.; Opara, Umezuruike L.

2016-02-01

Near infrared (NIR) spectroscopy has gained extensive use in quality evaluation. It is arguably one of the most advanced spectroscopic tools in non-destructive quality testing of food stuff, from measurement to data analysis and interpretation. NIR spectral data are interpreted through means often involving multivariate statistical analysis, sometimes associated with optimisation techniques for model improvement. The objective of this research was to explore the extent to which genetic algorithms (GA) can be used to enhance model development, for predicting fruit quality. Apple fruits were used, and NIR spectra in the range from 12000 to 4000 cm-1 were acquired on both bruised and healthy tissues, with different degrees of mechanical damage. GAs were used in combination with partial least squares regression methods to develop bruise severity prediction models, and compared to PLS models developed using the full NIR spectrum. A classification model was developed, which clearly separated bruised from unbruised apple tissue. GAs helped improve prediction models by over 10%, in comparison with full spectrum-based models, as evaluated in terms of error of prediction (Root Mean Square Error of Cross-validation). PLS models to predict internal quality, such as sugar content and acidity were developed and compared to the versions optimized by genetic algorithm. Overall, the results highlighted the potential use of GA method to improve speed and accuracy of fruit quality prediction.

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses.

PubMed

Ramkumar, Hema L; Gudiseva, Harini V; Kishaba, Kameron T; Suk, John J; Verma, Rohan; Tadimeti, Keerti; Thorson, John A; Ayyagari, Radha

2017-02-01

To test the utility of targeted sequencing as a method of clinical molecular testing in patients diagnosed with inherited retinal degeneration (IRD). After genetic counseling, peripheral blood was drawn from 188 probands and 36 carriers of IRD. Single gene testing was performed on each patient in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory. DNA was isolated, and all exons in the gene of interest were analyzed along with 20 base pairs of flanking intronic sequence. Genetic testing was most often performed on ABCA4, CTRP5, ELOV4, BEST1, CRB1, and PRPH2. Pathogenicity of novel sequence changes was predicted by PolyPhen2 and sorting intolerant from tolerant (SIFT). Of the 225 genetic tests performed, 150 were for recessive IRD, and 75 were for dominant IRD. A positive molecular diagnosis was made in 70 (59%) of probands with recessive IRD and 19 (26%) probands with dominant IRD. Analysis confirmed 12 (34%) of individuals as carriers of familial mutations associated with IRD. Thirty-two novel variants were identified; among these, 17 sequence changes in four genes were predicted to be possibly or probably damaging including: ABCA4 (14), BEST1 (2), PRPH2 (1), and TIMP3 (1). Targeted analysis of clinically suspected genes in 225 subjects resulted in a positive molecular diagnosis in 26% of patients with dominant IRD and 59% of patients with recessive IRD. Novel damaging mutations were identified in four genes. Single gene screening is not an ideal method for diagnostic testing given the phenotypic and genetic heterogeneity among IRD cases. High-throughput sequencing of all genes associated with retinal degeneration may be more efficient for molecular diagnosis.

Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French‐Canadian families with high risk of breast and ovarian cancer

PubMed Central

Simard, Jacques; Dumont, Martine; Moisan, Anne‐Marie; Gaborieau, Valérie; Vézina, Hélène; Durocher, Francine; Chiquette, Jocelyne; Plante, Marie; Avard, Denise; Bessette, Paul; Brousseau, Claire; Dorval, Michel; Godard, Béatrice; Houde, Louis; Joly, Yann; Lajoie, Marie‐Andrée; Leblanc, Gilles; Lépine, Jean; Lespérance, Bernard; Malouin, Hélène; Parboosingh, Jillian; Pichette, Roxane; Provencher, Louise; Rhéaume, Josée; Sinnett, Daniel; Samson, Carolle; Simard, Jean‐Claude; Tranchant, Martine; Voyer, Patricia; BRCAs, INHERIT; Easton, Douglas; Tavtigian, Sean V; Knoppers, Bartha‐Maria; Laframboise, Rachel; Bridge, Peter; Goldgar, David

2007-01-01

Background and objective In clinical settings with fixed resources allocated to predictive genetic testing for high‐risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French‐Canadian population of Quebec, Canada are reported. Methods A total of 256 high‐risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. Results 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2‐positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in ⩾2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1‐positive and 29 BRCA2‐positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores ⩾18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p<0.001). A threshold of Manchester Score ⩾18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population. Conclusion In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores ⩾18, represents an efficient test in terms of overall cost and sensitivity. PMID:16905680

Consumer preferences for the predictive genetic test for Alzheimer disease.

PubMed

Huang, Ming-Yi; Huston, Sally A; Perri, Matthew

2014-04-01

The purpose of this study was to assess consumer preferences for predictive genetic testing for Alzheimer disease in the United States. A rating conjoint analysis was conducted using an anonymous online survey distributed by Qualtrics to a general population panel in April 2011 in the United States. The study design included three attributes: Accuracy (40%, 80%, and 100%), Treatment Availability (Cure is available/Drug for symptom relief but no cure), and Anonymity (Anonymous/Not anonymous). A total of 12 scenarios were used to elicit people's preference, assessed by an 11-point scale. The respondents also indicated their highest willingness-to-pay (WTP) for each scenario through open-ended questions. A total of 295 responses were collected over 4 days. The most important attribute for the aggregate model was Accuracy, contributing 64.73% to the preference rating. Treatment Availability and Anonymity contributed 20.72% and 14.59%, respectively, to the preference rating. The median WTP for the highest-rating scenario (Accuracy 100%, a cure is available, test result is anonymous) was $100 (mean = $276). The median WTP for the lowest-rating scenario (40% accuracy, no cure but drugs for symptom relief, not anonymous) was zero (mean = $34). The results of this study highlight attributes people find important when making the hypothetical decision to obtain an AD genetic test. These results should be of interests to policy makers, genetic test developers and health care providers.

Genetic correlations of mid-infrared-predicted milk fatty acid groups with milk production traits.

PubMed

Fleming, A; Schenkel, F S; Malchiodi, F; Ali, R A; Mallard, B; Sargolzaei, M; Jamrozik, J; Johnston, J; Miglior, F

2018-05-01

The objective of this research was to estimate the genetic correlations between milk mid-infrared-predicted fatty acid groups and production traits in first-parity Canadian Holsteins. Contents of short-chain, medium-chain, long-chain, saturated, and unsaturated fatty acid groupings in milk samples can be predicted using mid-infrared spectral data for cows enrolled in milk recording programs. Predicted fatty acid group contents were obtained for 49,127 test-day milk samples from 10,029 first-parity Holstein cows in 810 herds. Milk yield, fat and protein yield, fat and protein percentage, fat-to-protein ratio, and somatic cell score were also available for these test days. Genetic parameters were estimated for the fatty acid groups and production traits using multiple-trait random regression test day models by Bayesian methods via Gibbs sampling. Three separate 8- or 9-trait analyses were performed, including the 5 fatty acid groups with different combinations of the production traits. Posterior standard deviations ranged from <0.001 to 0.01. Average daily genetic correlations were negative and similar to each other for the fatty acid groups with milk yield (-0.62 to -0.59) and with protein yield (-0.32 to -0.25). Weak and positive average daily genetic correlations were found between somatic cell score and the fatty acid groups (from 0.25 to 0.36). Stronger genetic correlations with fat yield, fat and protein percentage, and fat-to-protein ratio were found with medium-chain and saturated fatty acid groups compared with those with long-chain and unsaturated fatty acid groups. Genetic correlations were very strong between the fatty acid groups and fat percentage, ranging between 0.88 for unsaturated and 0.99 for saturated fatty acids. Daily genetic correlations from 5 to 305 d in milk with milk, protein yield and percentage, and somatic cell score traits showed similar patterns for all fatty acid groups. The daily genetic correlations with fat yield at the beginning of lactation were decreasing for long-chain and unsaturated fatty acid groups and increasing for short-chain fatty acids. Genetic correlations between fat percentage and fatty acids were increasing at the beginning of lactation for short- and medium-chain and saturated fatty acids, but slightly decreasing for long-chain and unsaturated fatty acid groups. These results can be used in defining fatty acid traits and breeding objectives. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data.

PubMed

He, Zihuai; Xu, Bin; Lee, Seunggeun; Ionita-Laza, Iuliana

2017-09-07

Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease-associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. Here, we have developed unified tests that can utilize multiple functional annotations simultaneously for integrative association analysis with efficient computational techniques. We show that the proposed tests significantly improve power when variant risk status can be predicted by functional annotations. Importantly, when functional annotations are not predictive of risk status, the proposed tests incur only minimal loss of power in relation to existing dispersion and burden tests, and under certain circumstances they can even have improved power by learning a weight that better approximates the underlying disease model in a data-adaptive manner. The tests can be constructed with summary statistics of existing dispersion and burden tests for sequencing data, therefore allowing meta-analysis of multiple studies without sharing individual-level data. We applied the proposed tests to a meta-analysis of noncoding rare variants in Metabochip data on 12,281 individuals from eight studies for lipid traits. By incorporating the Eigen functional score, we detected significant associations between noncoding rare variants in SLC22A3 and low-density lipoprotein and total cholesterol, associations that are missed by standard dispersion and burden tests. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Value of genetic profiling for the prediction of coronary heart disease.

PubMed

van der Net, Jeroen B; Janssens, A Cecile J W; Sijbrands, Eric J G; Steyerberg, Ewout W

2009-07-01

Advances in high-throughput genomics facilitate the identification of novel genetic susceptibility variants for coronary heart disease (CHD). This may improve CHD risk prediction. The aim of the present simulation study was to investigate to what degree CHD risk can be predicted by testing multiple genetic variants (genetic profiling). We simulated genetic profiles for a population of 100,000 individuals with a 10-year CHD incidence of 10%. For each combination of model parameters (number of variants, genotype frequency and odds ratio [OR]), we calculated the area under the receiver operating characteristic curve (AUC) to indicate the discrimination between individuals who will and will not develop CHD. The AUC of genetic profiles could rise to 0.90 when 100 hypothetical variants with ORs of 1.5 and genotype frequencies of 50% were simulated. The AUC of a genetic profile consisting of 10 established variants, with ORs ranging from 1.13 to 1.42, was 0.59. When 2, 5, and 10 times as many identical variants would be identified, the AUCs were 0.63, 0.69, and 0.76. To obtain AUCs similar to those of conventional CHD risk predictors, a considerable number of additional common genetic variants need to be identified with preferably strong effects.

Predictive genetic tests: problems and pitfalls.

PubMed

Davis, J G

1997-12-29

The role that genetic factors play in medicine has expanded, owing to such recent advances as those made by the Human Genome Project and the work that has spun off from it. The project is focusing particularly on localization and characterization of recognized human genetic disorders, which in turn increases awareness of the potential for improved treatment of these disorders. Technical advances in genetic testing in the absence of effective treatment has presented the health profession with major ethical challenges. The example of the identification of the BRCA1 and BRCA2 genes in families at high risk for breast and ovarian cancer is presented to illustrate the issues of the sensitivity of the method, the degree of susceptibility a positive result implies, the need for and availability of counseling and patient education, and confidentiality of the test results. A compelling need exists for adequate education about medical genetics to raise the "literacy" rate among health professionals.

Let the consumer decide? The regulation of commercial genetic testing

PubMed Central

Levitt, D. M.

2001-01-01

Objectives—The development of predictive genetic tests provides a new area where consumers can gain knowledge of their health status and commercial opportunities. "Over-the-counter" or mail order genetic tests are most likely to provide information on carrier status or the risk of developing a multifactorial disease. The paper considers the social and ethical implications of individuals purchasing genetic tests and whether genetic information is different from other types of health information which individuals can obtain for themselves. Design—The discussion is illustrated by findings from a questionnaire survey of university students as potential consumers. Topics covered included what health tests they had already used, expectations of genetic tests, willingness to pay, who should have access to the results and whether there need to be restrictions on such tests. Sample—Six hundred and fifteen first-year students in the universities of Leuven, Cardiff, Central Lancashire, Vienna and Nijmegen studying either medicine or a non-science subject. Results—Students were enthusiastic about genetic tests and had high expectations of their accuracy and usefulness but most thought they should be available through the health service and a minority thought that some tests, for example for sex selection, should not be available at all. There were few differences in responses by sex or subject of study but some by country. The paper also considers ethical and social issues outside the scope of a questionnaire survey of this type. Conclusion—To address some of these issues the sale of genetic tests to individuals can be made subject to ethical guidelines or codes of practice, for example to protect vulnerable groups, but there are fundamental social and ethical questions which such guidelines cannot address. Key Words: Genetic tests • European • commercialisation PMID:11731604

Realized gain from breeding Eucalyptus grandis in Florida

Treesearch

George Meskimen

1983-01-01

E. grandis is in the fourth generation of selection in southwest Florida. The breeding strategy combines a provenance trial, genetic base population, seedling seed orchard, and progeny test in a single plantation where all families are completely randomized in single-tree plots. That planting configuration closely predicted the magnitude of genetic...

Genetic relations among procrastination, impulsivity, and goal-management ability: implications for the evolutionary origin of procrastination.

PubMed

Gustavson, Daniel E; Miyake, Akira; Hewitt, John K; Friedman, Naomi P

2014-06-01

Previous research has revealed a moderate and positive correlation between procrastination and impulsivity. However, little is known about why these two constructs are related. In the present study, we used behavior-genetics methodology to test three predictions derived from an evolutionary account that postulates that procrastination arose as a by-product of impulsivity: (a) Procrastination is heritable, (b) the two traits share considerable genetic variation, and (c) goal-management ability is an important component of this shared variation. These predictions were confirmed. First, both procrastination and impulsivity were moderately heritable (46% and 49%, respectively). Second, although the two traits were separable at the phenotypic level (r = .65), they were not separable at the genetic level (r genetic = 1.0). Finally, variation in goal-management ability accounted for much of this shared genetic variation. These results suggest that procrastination and impulsivity are linked primarily through genetic influences on the ability to use high-priority goals to effectively regulate actions. © The Author(s) 2014.

Molecular Testing of Brain Tumor

PubMed Central

Park, Sung-Hye; Won, Jaekyung; Kim, Seong-Ik; Lee, Yujin; Park, Chul-Kee; Kim, Seung-Ki; Choi, Seung-Hong

2017-01-01

The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp. High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors. PMID:28535583

Impact of presymptomatic genetic testing on young adults: a systematic review.

PubMed

Godino, Lea; Turchetti, Daniela; Jackson, Leigh; Hennessy, Catherine; Skirton, Heather

2016-04-01

Presymptomatic and predictive genetic testing should involve a considered choice, which is particularly true when testing is undertaken in early adulthood. Young adults are at a key life stage as they may be developing a career, forming partnerships and potentially becoming parents: presymptomatic testing may affect many facets of their future lives. The aim of this integrative systematic review was to assess factors that influence young adults' or adolescents' choices to have a presymptomatic genetic test and the emotional impact of those choices. Peer-reviewed papers published between January 1993 and December 2014 were searched using eight databases. Of 3373 studies identified, 29 were reviewed in full text: 11 met the inclusion criteria. Thematic analysis was used to identify five major themes: period before testing, experience of genetic counselling, parental involvement in decision-making, impact of test result communication, and living with genetic risk. Many participants grew up with little or no information concerning their genetic risk. The experience of genetic counselling was either reported as an opportunity for discussing problems or associated with feelings of disempowerment. Emotional outcomes of disclosure did not directly correlate with test results: some mutation carriers were relieved to know their status, however, the knowledge they may have passed on the mutation to their children was a common concern. Parents appeared to have exerted pressure on their children during the decision-making process about testing and risk reduction surgery. Health professionals should take into account all these issues to effectively assist young adults in making decisions about presymptomatic genetic testing.

Polygenic scores predict alcohol problems in an independent sample and show moderation by the environment.

PubMed

Salvatore, Jessica E; Aliev, Fazil; Edwards, Alexis C; Evans, David M; Macleod, John; Hickman, Matthew; Lewis, Glyn; Kendler, Kenneth S; Loukola, Anu; Korhonen, Tellervo; Latvala, Antti; Rose, Richard J; Kaprio, Jaakko; Dick, Danielle M

2014-04-10

Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants do not. In the current study, we first tested whether polygenic risk for alcohol problems-derived from genome-wide association estimates of an alcohol problems factor score from the age 18 assessment of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4304 individuals of European descent; 57% female)-predicted alcohol problems earlier in development (age 14) in an independent sample (FinnTwin12; n = 1162; 53% female). We then tested whether environmental factors (parental knowledge and peer deviance) moderated polygenic risk to predict alcohol problems in the FinnTwin12 sample. We found evidence for both polygenic association and for additive polygene-environment interaction. Higher polygenic scores predicted a greater number of alcohol problems (range of Pearson partial correlations 0.07-0.08, all p-values ≤ 0.01). Moreover, genetic influences were significantly more pronounced under conditions of low parental knowledge or high peer deviance (unstandardized regression coefficients (b), p-values (p), and percent of variance (R2) accounted for by interaction terms: b = 1.54, p = 0.02, R2 = 0.33%; b = 0.94, p = 0.04, R2 = 0.30%, respectively). Supplementary set-based analyses indicated that the individual top single nucleotide polymorphisms (SNPs) contributing to the polygenic scores were not individually enriched for gene-environment interaction. Although the magnitude of the observed effects are small, this study illustrates the usefulness of polygenic approaches for understanding the pathways by which measured genetic predispositions come together with environmental factors to predict complex behavioral outcomes.

Predictive testing and existential absurdity: resonances between experiences around genetic diagnosis and the philosophy of Albert Camus.

PubMed

Porz, Rouven; Widdershoven, Guy

2011-07-01

Predictive genetic testing may confront those affected with difficult life situations that they have not experienced before. These life situations may be interpreted as 'absurd'. In this paper we present a case study of a predictive test situation, showing the perspective of a woman going through the process of deciding for or against taking the test, and struggling with feelings of alienation. To interpret her experiences, we refer to the concept of absurdity, developed by the French Philosopher Albert Camus. Camus' writings on absurdity appear to resonate with patients' stories when they talk about their body and experiences of illness. In this paper we draw on Camus' philosophical essay 'The Myth of Sisyphus' (1942), and compare the absurd experiences of Sisyphus with the interviewee's story. This comparison opens up a field of ethical reflection. We demonstrate that Camus' concept of absurdity offers a new and promising approach to understanding the fragility of patients' situations, especially in the field of predictive testing. We show that people affected might find new meaning through narratives that help them to reconstruct the absurd without totally overcoming it. In conclusion, we will draw out some normative consequences of our narrative approach. © 2009 Blackwell Publishing Ltd.

Expansion of genetic testing in the division of functional genomics, research center for bioscience and technology, tottori university from 2000 to 2013.

PubMed

Adachi, Kaori

2014-03-01

At the Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, we have been making an effort to establish a genetic testing facility that can provide the same screening procedures conducted worldwide. Direct Sequencing of PCR products is the main method to detect point mutations, small deletions and insertions. Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect large deletions or insertions. Expansion of the repeat was analyzed for triplet repeat diseases. Original primers were constructed for 41 diseases when the reported primers failed to amplify the gene. Prediction of functional effects of human nsSNPs (PolyPhen) was used for evaluation of novel mutations. From January 2000 to September 2013, a total of 1,006 DNA samples were subjected to genetic testing in the Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University. The hospitals that requested genetic testing were located in 43 prefectures in Japan and in 11 foreign countries. The genetic testing covered 62 diseases, and mutations were detected in 287 out of 1,006 with an average mutation detection rate of 24.7%. There were 77 samples for prenatal diagnosis. The number of samples has rapidly increased since 2010. In 2013, the next-generation sequencers were introduced in our facility and are expected to provide more comprehensive genetic testing in the near future. Nowadays, genetic testing is a popular and powerful tool for diagnosis of many genetic diseases. Our genetic testing should be further expanded in the future.

"Would you test your children without their consent?" and other sticky dilemmas in the field of cancer genetic testing.

PubMed

Brierley, Karina L; Bonadies, Danielle C; Moyer, Anne; Matloff, Ellen T

2014-09-01

Cancer genetic testing is surrounded by myriad ethical, legal, and psychosocial implications which are being revisited as testing expands into an everyday practice and into more complicated areas like whole exome and direct-to-consumer testing. We chose to survey cancer genetic counselors and physicians from a wide range of non-genetics specialties to determine what they would do if faced with the complex decisions associated with cancer genetic testing, how their views compare, and how they align with current guidelines and data. Genetic counselors were significantly more likely than non-genetics physicians to bill their insurance for testing (94.9 vs. 86.8 %; p = 0.001) and purchase life insurance before testing (86.6 vs. 68.6 %; p = 0.000) and were less likely to use an alias (3.2 vs. 13.2 %; p = 0.000) or order testing on their own DNA (15.3 vs. 24.2 %; p = 0.004). They were also less likely to test their minor children (0.9 vs. 33.1 %; p = 0.000) or test their children without their knowledge and consent/assent (1.4 vs.11.5 %; p = 0.000). The results of our study indicate that there is wide variation regarding what clinicians predict they would do in the areas of ethical, legal and psychosocial issues in cancer genetic testing. Cancer genetic counselors' choices are more aligned with professional guidelines, likely due to their experience in the field and awareness of current guidelines. These data are a starting point for a broader discussion of who should offer cancer genetic counseling and testing to patients, particularly as the complexity of the available testing options and associated issues increase with whole exome sequencing.

Lay perceptions of predictive testing for diabetes based on DNA test results versus family history assessment: a focus group study.

PubMed

Wijdenes-Pijl, Miranda; Dondorp, Wybo J; Timmermans, Danielle Rm; Cornel, Martina C; Henneman, Lidewij

2011-07-05

This study assessed lay perceptions of issues related to predictive genetic testing for multifactorial diseases. These perceived issues may differ from the "classic" issues, e.g. autonomy, discrimination, and psychological harm that are considered important in predictive testing for monogenic disorders. In this study, type 2 diabetes was used as an example, and perceptions with regard to predictive testing based on DNA test results and family history assessment were compared. Eight focus group interviews were held with 45 individuals aged 35-70 years with (n = 3) and without (n = 1) a family history of diabetes, mixed groups of these two (n = 2), and diabetes patients (n = 2). All interviews were transcribed and analysed using Atlas-ti. Most participants believed in the ability of a predictive test to identify people at risk for diabetes and to motivate preventive behaviour. Different reasons underlying motivation were considered when comparing DNA test results and a family history risk assessment. A perceived drawback of DNA testing was that diabetes was considered not severe enough for this type of risk assessment. In addition, diabetes family history assessment was not considered useful by some participants, since there are also other risk factors involved, not everyone has a diabetes family history or knows their family history, and it might have a negative influence on family relations. Respect for autonomy of individuals was emphasized more with regard to DNA testing than family history assessment. Other issues such as psychological harm, discrimination, and privacy were only briefly mentioned for both tests. The results suggest that most participants believe a predictive genetic test could be used in the prevention of multifactorial disorders, such as diabetes, but indicate points to consider before both these tests are applied. These considerations differ with regard to the method of assessment (DNA test or obtaining family history) and also differ from monogenic disorders.

Comparative Study on Prediction Effects of Short Fatigue Crack Propagation Rate by Two Different Calculation Methods

NASA Astrophysics Data System (ADS)

Yang, Bing; Liao, Zhen; Qin, Yahang; Wu, Yayun; Liang, Sai; Xiao, Shoune; Yang, Guangwu; Zhu, Tao

2017-05-01

To describe the complicated nonlinear process of the fatigue short crack evolution behavior, especially the change of the crack propagation rate, two different calculation methods are applied. The dominant effective short fatigue crack propagation rates are calculated based on the replica fatigue short crack test with nine smooth funnel-shaped specimens and the observation of the replica films according to the effective short fatigue cracks principle. Due to the fast decay and the nonlinear approximation ability of wavelet analysis, the self-learning ability of neural network, and the macroscopic searching and global optimization of genetic algorithm, the genetic wavelet neural network can reflect the implicit complex nonlinear relationship when considering multi-influencing factors synthetically. The effective short fatigue cracks and the dominant effective short fatigue crack are simulated and compared by the Genetic Wavelet Neural Network. The simulation results show that Genetic Wavelet Neural Network is a rational and available method for studying the evolution behavior of fatigue short crack propagation rate. Meanwhile, a traditional data fitting method for a short crack growth model is also utilized for fitting the test data. It is reasonable and applicable for predicting the growth rate. Finally, the reason for the difference between the prediction effects by these two methods is interpreted.

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement

PubMed Central

Webborn, Nick; Williams, Alun; McNamee, Mike; Bouchard, Claude; Pitsiladis, Yannis; Ahmetov, Ildus; Ashley, Euan; Byrne, Nuala; Camporesi, Silvia; Collins, Malcolm; Dijkstra, Paul; Eynon, Nir; Fuku, Noriyuki; Garton, Fleur C; Hoppe, Nils; Holm, Søren; Kaye, Jane; Klissouras, Vassilis; Lucia, Alejandro; Maase, Kamiel; Moran, Colin; North, Kathryn N; Pigozzi, Fabio; Wang, Guan

2015-01-01

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. PMID:26582191

Increased genomic prediction accuracy in wheat breeding using a large Australian panel.

PubMed

Norman, Adam; Taylor, Julian; Tanaka, Emi; Telfer, Paul; Edwards, James; Martinant, Jean-Pierre; Kuchel, Haydn

2017-12-01

Genomic prediction accuracy within a large panel was found to be substantially higher than that previously observed in smaller populations, and also higher than QTL-based prediction. In recent years, genomic selection for wheat breeding has been widely studied, but this has typically been restricted to population sizes under 1000 individuals. To assess its efficacy in germplasm representative of commercial breeding programmes, we used a panel of 10,375 Australian wheat breeding lines to investigate the accuracy of genomic prediction for grain yield, physical grain quality and other physiological traits. To achieve this, the complete panel was phenotyped in a dedicated field trial and genotyped using a custom Axiom TM Affymetrix SNP array. A high-quality consensus map was also constructed, allowing the linkage disequilibrium present in the germplasm to be investigated. Using the complete SNP array, genomic prediction accuracies were found to be substantially higher than those previously observed in smaller populations and also more accurate compared to prediction approaches using a finite number of selected quantitative trait loci. Multi-trait genetic correlations were also assessed at an additive and residual genetic level, identifying a negative genetic correlation between grain yield and protein as well as a positive genetic correlation between grain size and test weight.

Psychosocial impact of prognostic genetic testing in the care of uveal melanoma patients: protocol of a controlled prospective clinical observational study.

PubMed

Erim, Yesim; Scheel, Jennifer; Breidenstein, Anja; Metz, Claudia Hd; Lohmann, Dietmar; Friederich, Hans-Christoph; Tagay, Sefik

2016-07-07

Uveal melanoma patients with a poor prognosis can be detected through genetic analysis of the tumor, which has a very high sensitivity. A large number of patients with uveal melanoma decide to receive information about their individual risk and therefore routine prognostic genetic testing is being carried out on a growing number of patients. It is obvious that a positive prediction for recidivism in the future will emotionally burden the respective patients, but research on the psychosocial impact of this innovative method is lacking. The aim of the current study is therefore to investigate the psychosocial impact (psychological distress and quality of life) of prognostic genetic testing in patients with uveal melanoma. This study is a non-randomized controlled prospective clinical observational trial. Subjects are patients with uveal melanoma, in whom genetic testing is possible. Patients who consent to genetic testing are allocated to the intervention group and patients who refuse genetic testing form the observational group. Both groups receive cancer therapy and psycho-oncological intervention when needed. The psychosocial impact of prognostic testing is investigated with the following variables: resilience, social support, fear of tumor progression, depression, general distress, cancer-specific and general health-related quality of life, attitude towards genetic testing, estimation of the perceived risk of metastasis, utilization and satisfaction with psycho-oncological crisis intervention, and sociodemographic data. Data are assessed preoperatively (at initial admission in the clinic) and postoperatively (at discharge from hospital after surgery, 6-12 weeks, 6 and 12 months after initial admission). Genetic test results are communicated 6-12 weeks after initial admission to the clinic. We created optimal conditions for investigation of the psychosocial impact of prognostic genetic testing. This study will provide information on the course of disease and psychosocial outcomes after prognostic genetic testing. We expect that empirical data from our study will give a scientific basis for medico-ethical considerations.

Using genetics to predict the natural history of asthma?

PubMed

Holloway, John W; Arshad, Syed H; Holgate, Stephen T

2010-08-01

Clinical practice reminds us that there is considerable variability in the course of asthma over time. Treatment of patients with asthma would be considerably improved if one could accurately predict the likely course of disease over the life course. Recently, with the advent of the era of genome-wide association studies, there has been a monumental shift in our understanding of the genetic factors that underlie inherited susceptibility to asthma. Genes have been identified that modulate many aspects of the natural history of asthma, such as susceptibility to atopy, altered lung development, and susceptibility to more severe disease. Heritability studies have even suggested a role for genetic factors in remission of asthma. However, although the discovery of novel genetic factors underlying disease susceptibility has undoubtedly improved our understanding of disease pathogenesis, whether these advances have improved the ability to predict the natural history in individual patients is questionable, and the application of genetic testing to clinical practice remains some way off. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Intention to communicate BRCA1/BRCA2 genetic test results to the family.

PubMed

Barsevick, Andrea M; Montgomery, Susan V; Ruth, Karen; Ross, Eric A; Egleston, Brian L; Bingler, Ruth; Malick, John; Miller, Suzanne M; Cescon, Terrence P; Daly, Mary B

2008-04-01

Guided by the theory of planned behavior, this analysis explores the communication skills of women who had genetic testing for BRCA1 and BRCA2. The key outcome was intention to tell test results to adult first-degree relatives. The theory predicts that global and specific attitudes, global and specific perceived social norms, and perceived control will influence the communication of genetic test results. A logistic regression model revealed that global attitude (p < .05), specific social influence (p < .01), and perceived control (p < .05) were significant predictors of intention to tell. When gender and generation of relatives were added to the regression, participants were more likely to convey genetic test results to female than to male relatives (p < .05) and were also more likely to communicate test results to children (p < .01) or siblings (p < .05) than to parents. However, this association depended on knowing the relative's opinion of genetic testing. Intention to tell was lowest among participants who did not know their relative's opinion. These results extend the theory of planned behavior by showing that gender and generation influence intention when the relative's opinion is unknown. (c) 2008 APA, all rights reserved.

Assessment of genetic and nongenetic interactions for the prediction of depressive symptomatology: an analysis of the Wisconsin Longitudinal Study using machine learning algorithms.

PubMed

Roetker, Nicholas S; Page, C David; Yonker, James A; Chang, Vicky; Roan, Carol L; Herd, Pamela; Hauser, Taissa S; Hauser, Robert M; Atwood, Craig S

2013-10-01

We examined depression within a multidimensional framework consisting of genetic, environmental, and sociobehavioral factors and, using machine learning algorithms, explored interactions among these factors that might better explain the etiology of depressive symptoms. We measured current depressive symptoms using the Center for Epidemiologic Studies Depression Scale (n = 6378 participants in the Wisconsin Longitudinal Study). Genetic factors were 78 single nucleotide polymorphisms (SNPs); environmental factors-13 stressful life events (SLEs), plus a composite proportion of SLEs index; and sociobehavioral factors-18 personality, intelligence, and other health or behavioral measures. We performed traditional SNP associations via logistic regression likelihood ratio testing and explored interactions with support vector machines and Bayesian networks. After correction for multiple testing, we found no significant single genotypic associations with depressive symptoms. Machine learning algorithms showed no evidence of interactions. Naïve Bayes produced the best models in both subsets and included only environmental and sociobehavioral factors. We found no single or interactive associations with genetic factors and depressive symptoms. Various environmental and sociobehavioral factors were more predictive of depressive symptoms, yet their impacts were independent of one another. A genome-wide analysis of genetic alterations using machine learning methodologies will provide a framework for identifying genetic-environmental-sociobehavioral interactions in depressive symptoms.

Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

PubMed

Tansey, Katherine E; Guipponi, Michel; Perroud, Nader; Bondolfi, Guido; Domenici, Enrico; Evans, David; Hall, Stephanie K; Hauser, Joanna; Henigsberg, Neven; Hu, Xiaolan; Jerman, Borut; Maier, Wolfgang; Mors, Ole; O'Donovan, Michael; Peters, Tim J; Placentino, Anna; Rietschel, Marcella; Souery, Daniel; Aitchison, Katherine J; Craig, Ian; Farmer, Anne; Wendland, Jens R; Malafosse, Alain; Holmans, Peter; Lewis, Glyn; Lewis, Cathryn M; Stensbøl, Tine Bryan; Kapur, Shitij; McGuffin, Peter; Uher, Rudolf

2012-01-01

It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe

PubMed Central

Hastings, Ros; de Wert, Guido; Fowler, Brian; Krawczak, Michael; Vermeulen, Eric; Bakker, Egbert; Borry, Pascal; Dondorp, Wybo; Nijsingh, Niels; Barton, David; Schmidtke, Jörg; van El, Carla G; Vermeesch, Joris; Stol, Yrrah; Carmen Howard, Heidi; Cornel, Martina C

2012-01-01

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the ‘Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research. PMID:22453292

The Double Helix: Applying an Ethic of Care to the Duty to Warn Genetic Relatives of Genetic Information.

PubMed

Weaver, Meaghann

2016-03-01

Genetic testing reveals information about a patient's health status and predictions about the patient's future wellness, while also potentially disclosing health information relevant to other family members. With the increasing availability and affordability of genetic testing and the integration of genetics into mainstream medicine, the importance of clarifying the scope of confidentiality and the rules regarding disclosure of genetic findings to genetic relatives is prime. The United Nations International Declaration on Human Genetic Data urges an appreciation for principles of equality, justice, solidarity and responsibility in the context of genetic testing, including a commitment to honoring the privacy and security of the person tested. Considering this global mandate and recent professional statements in the context of a legal amendment to patient privacy policies in Australia, a fresh scrutiny of the legal history of a physician's duty to warn is warranted. This article inquiries whether there may be anything ethically or socially amiss with a potential future recommendation for health professionals or patients to universally disclose particular cancer predisposition genetic diagnosis to genetic family members. While much of the discussion remains applicable to all genetic diagnosis, the article focuses on the practice of disclosure within the context of BRCA1/2 diagnosis. An 'ethic of care' interpretation of legal tradition and current practice will serve to reconcile law and medical policy on the issue of physician disclosure of genetic results to family members without patient consent. © 2015 John Wiley & Sons Ltd.

The Bell Curve Revisited: Testing Controversial Hypotheses with Molecular Genetic Data

PubMed Central

Conley, Dalton; Domingue, Benjamin

2017-01-01

In 1994, the publication of Herrnstein’s and Murray’s The Bell Curve resulted in a social science maelstrom of responses. In the present study, we argue that Herrnstein’s and Murray’s assertions were made prematurely, on their own terms, given the lack of data available to test the role of genotype in the dynamics of achievement and attainment in U.S. society. Today, however, the scientific community has access to at least one dataset that is nationally representative and has genome-wide molecular markers. We deploy those data from the Health and Retirement Study in order to test the core series of propositions offered by Herrnstein and Murray in 1994. First, we ask whether the effect of genotype is increasing in predictive power across birth cohorts in the middle twentieth century. Second, we ask whether assortative mating on relevant genotypes is increasing across the same time period. Finally, we ask whether educational genotypes are increasingly predictive of fertility (number ever born [NEB]) in tandem with the rising (negative) association of educational outcomes and NEB. The answers to these questions are mostly no; while molecular genetic markers can predict educational attainment, we find little evidence for the proposition that we are becoming increasingly genetically stratified. PMID:29130056

Predicting Landscape-Genetic Consequences of Habitat Loss, Fragmentation and Mobility for Multiple Species of Woodland Birds

PubMed Central

Amos, J. Nevil; Bennett, Andrew F.; Mac Nally, Ralph; Newell, Graeme; Pavlova, Alexandra; Radford, James Q.; Thomson, James R.; White, Matt; Sunnucks, Paul

2012-01-01

Inference concerning the impact of habitat fragmentation on dispersal and gene flow is a key theme in landscape genetics. Recently, the ability of established approaches to identify reliably the differential effects of landscape structure (e.g. land-cover composition, remnant vegetation configuration and extent) on the mobility of organisms has been questioned. More explicit methods of predicting and testing for such effects must move beyond post hoc explanations for single landscapes and species. Here, we document a process for making a priori predictions, using existing spatial and ecological data and expert opinion, of the effects of landscape structure on genetic structure of multiple species across replicated landscape blocks. We compare the results of two common methods for estimating the influence of landscape structure on effective distance: least-cost path analysis and isolation-by-resistance. We present a series of alternative models of genetic connectivity in the study area, represented by different landscape resistance surfaces for calculating effective distance, and identify appropriate null models. The process is applied to ten species of sympatric woodland-dependant birds. For each species, we rank a priori the expectation of fit of genetic response to the models according to the expected response of birds to loss of structural connectivity and landscape-scale tree-cover. These rankings (our hypotheses) are presented for testing with empirical genetic data in a subsequent contribution. We propose that this replicated landscape, multi-species approach offers a robust method for identifying the likely effects of landscape fragmentation on dispersal. PMID:22363508

The use of genetic information in the insurance sector--a German perspective.

PubMed

Armbrüster, Christian; Obal, Monika

2013-01-01

The following paper offers an introduction to the legal framework concerning the use of genetic information in the insurance sector in Germany. The main contents and the controversial issues of the key regulation are examined. The aim of this rule being to secure human dignity by respecting the right to informational self-determination regarding genetic data, including the individual's right not to know about their genetic characteristics, there are a number of open issues which are being addressed. For instance, the influence of the prohibition to ask for genetic testing and to use the results of any such testing by the insurer is examined. This examination leads to some explicit results, such as the assumption that in addition to the ban on the use of genetic testing no questions about family medical history are admissible. The authors embark on the definition of genetic testing and the question to what extent the results of diagnostic genetic testing may still be made use of in the context of the insured person's obligation to display pre-existing conditions and diseases when the contract is concluded. In this respect distinctions between diagnostic and predictive genetic testing as well as between disease and disposition are drawn. Furthermore, the exceptions from the prohibition to use results of genetic testing are examined, and the scope of the prohibition of acceptance of results of genetic testing even if performed at the instigation of the insured is explored. Finally the consequences, encompassing criminal liability and private law ramifications, of the violation of the prohibition are presented. In this context, a narrow understanding of the aggravated criminal offence of using results of genetic testing with the intent to personal enrichment or in return for payments is developed. Finally the effects on the validity of the insurance contract and the question whether the insurer may be forced to conclude a contract are examined.

A genomic perspective on the generation and maintenance of genetic diversity in herbivorous insects

PubMed Central

Gloss, Andrew D.; Groen, Simon C.; Whiteman, Noah K.

2017-01-01

Understanding the processes that generate and maintain genetic variation within populations is a central goal in evolutionary biology. Theory predicts that some of this variation is maintained as a consequence of adapting to variable habitats. Studies in herbivorous insects have played a key role in confirming this prediction. Here, we highlight theoretical and conceptual models for the maintenance of genetic diversity in herbivorous insects, empirical genomic studies testing these models, and pressing questions within the realm of evolutionary and functional genomic studies. To address key gaps, we propose an integrative approach combining population genomic scans for adaptation, genome-wide characterization of targets of selection through experimental manipulations, mapping the genetic architecture of traits influencing fitness, and functional studies. We also stress the importance of studying the maintenance of genetic variation across biological scales—from variation within populations to divergence among populations—to form a comprehensive view of adaptation in herbivorous insects. PMID:28736510

Automated design of genetic toggle switches with predetermined bistability.

PubMed

Chen, Shuobing; Zhang, Haoqian; Shi, Handuo; Ji, Weiyue; Feng, Jingchen; Gong, Yan; Yang, Zhenglin; Ouyang, Qi

2012-07-20

Synthetic biology aims to rationally construct biological devices with required functionalities. Methods that automate the design of genetic devices without post-hoc adjustment are therefore highly desired. Here we provide a method to predictably design genetic toggle switches with predetermined bistability. To accomplish this task, a biophysical model that links ribosome binding site (RBS) DNA sequence to toggle switch bistability was first developed by integrating a stochastic model with RBS design method. Then, to parametrize the model, a library of genetic toggle switch mutants was experimentally built, followed by establishing the equivalence between RBS DNA sequences and switch bistability. To test this equivalence, RBS nucleotide sequences for different specified bistabilities were in silico designed and experimentally verified. Results show that the deciphered equivalence is highly predictive for the toggle switch design with predetermined bistability. This method can be generalized to quantitative design of other probabilistic genetic devices in synthetic biology.

Predictive genetic testing in children: constitutional mismatch repair deficiency cancer predisposing syndrome.

PubMed

Bruwer, Zandrè; Algar, Ursula; Vorster, Alvera; Fieggen, Karen; Davidson, Alan; Goldberg, Paul; Wainwright, Helen; Ramesar, Rajkumar

2014-04-01

Biallelic germline mutations in mismatch repair genes predispose to constitutional mismatch repair deficiency syndrome (CMMR-D). The condition is characterized by a broad spectrum of early-onset tumors, including hematological, brain and bowel and is frequently associated with features of Neurofibromatosis type 1. Few definitive screening recommendations have been suggested and no published reports have described predictive testing. We report on the first case of predictive testing for CMMR-D following the identification of two non-consanguineous parents, with the same heterozygous mutation in MLH1: c.1528C > T. The genetic counseling offered to the family, for their two at-risk daughters, is discussed with a focus on the ethical considerations of testing children for known cancer-causing variants. The challenges that are encountered when reporting on heterozygosity in a child younger than 18 years (disclosure of carrier status and risk for Lynch syndrome), when discovered during testing for homozygosity, are addressed. In addition, the identification of CMMR-D in a three year old, and the recommended clinical surveillance that was proposed for this individual is discussed. Despite predictive testing and presymptomatic screening, the sudden death of the child with CMMR-D syndrome occurred 6 months after her last surveillance MRI. This report further highlights the difficulty of developing guidelines, as a result of the rarity of cases and diversity of presentation.

Are public health professionals prepared for public health genomics? A cross-sectional survey in Italy

PubMed Central

2014-01-01

Background Public health genomics is an emerging multidisciplinary approach, which aims to integrate genome-based knowledge in a responsible and effective way into public health. Despite several surveys performed to evaluate knowledge, attitudes and professional behaviors of physicians towards predictive genetic testing, similar surveys have not been carried out for public health practitioners. This study is the first to assess knowledge, attitudes and training needs of public health professionals in the field of predictive genetic testing for chronic diseases. Methods A self-administered questionnaire was used to carry out a cross-sectional survey of a random sample of Italian public health professionals. Results A response rate of 67.4% (797 questionnaires) was achieved. Italian public health professionals have the necessary attitudinal background to contribute to the proper use of predictive genetic testing for chronic diseases, but they need additional training to increase their methodological knowledge. Knowledge significantly increases with exposure to predictive genetic testing during postgraduate training (odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.05–2.88), time dedicated to continuing medical education (OR = 1.53, 95% CI = 1.14–2.04) and level of English language knowledge (OR = 1.36, 95% CI = 1.07–1.72). Adequate knowledge is the strongest predictor of positive attitudes from a public health perspective (OR = 3.98, 95% CI = 2.44–6.50). Physicians show a lower level of knowledge and more public health attitudes than other public health professionals do. About 80% of public health professionals considered their knowledge inadequate and 86.0% believed that it should be improved through specific postgraduate training courses. Conclusions Specific and targeted training initiatives are needed to develop a skilled public health workforce competent in identifying genomic technology that is ready for use in population health and in modeling public health genomic programs and primary care services that need to be developed, implemented and evaluated. PMID:24885316

A new era in clinical genetic testing for hypertrophic cardiomyopathy.

PubMed

Wheeler, Matthew; Pavlovic, Aleksandra; DeGoma, Emil; Salisbury, Heidi; Brown, Colleen; Ashley, Euan A

2009-12-01

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

Breeding Jatropha curcas by genomic selection: A pilot assessment of the accuracy of predictive models.

PubMed

Azevedo Peixoto, Leonardo de; Laviola, Bruno Galvêas; Alves, Alexandre Alonso; Rosado, Tatiana Barbosa; Bhering, Leonardo Lopes

2017-01-01

Genomic wide selection is a promising approach for improving the selection accuracy in plant breeding, particularly in species with long life cycles, such as Jatropha. Therefore, the objectives of this study were to estimate the genetic parameters for grain yield (GY) and the weight of 100 seeds (W100S) using restricted maximum likelihood (REML); to compare the performance of GWS methods to predict GY and W100S; and to estimate how many markers are needed to train the GWS model to obtain the maximum accuracy. Eight GWS models were compared in terms of predictive ability. The impact that the marker density had on the predictive ability was investigated using a varying number of markers, from 2 to 1,248. Because the genetic variance between evaluated genotypes was significant, it was possible to obtain selection gain. All of the GWS methods tested in this study can be used to predict GY and W100S in Jatropha. A training model fitted using 1,000 and 800 markers is sufficient to capture the maximum genetic variance and, consequently, maximum prediction ability of GY and W100S, respectively. This study demonstrated the applicability of genome-wide prediction to identify useful genetic sources of GY and W100S for Jatropha breeding. Further research is needed to confirm the applicability of the proposed approach to other complex traits.

Postglacial recolonization in a cold climate specialist in western Europe: patterns of genetic diversity in the adder (Vipera berus) support the central-marginal hypothesis.

PubMed

Ursenbacher, Sylvain; Guillon, Michaël; Cubizolle, Hervé; Dupoué, Andréaz; Blouin-Demers, Gabriel; Lourdais, Olivier

2015-07-01

Understanding the impact of postglacial recolonization on genetic diversity is essential in explaining current patterns of genetic variation. The central-marginal hypothesis (CMH) predicts a reduction in genetic diversity from the core of the distribution to peripheral populations, as well as reduced connectivity between peripheral populations. While the CMH has received considerable empirical support, its broad applicability is still debated and alternative hypotheses predict different spatial patterns of genetic diversity. Using microsatellite markers, we analysed the genetic diversity of the adder (Vipera berus) in western Europe to reconstruct postglacial recolonization. Approximate Bayesian Computation (ABC) analyses suggested a postglacial recolonization from two routes: a western route from the Atlantic Coast up to Belgium and a central route from the Massif Central to the Alps. This cold-adapted species likely used two isolated glacial refugia in southern France, in permafrost-free areas during the last glacial maximum. Adder populations further from putative glacial refugia had lower genetic diversity and reduced connectivity; therefore, our results support the predictions of the CMH. Our study also illustrates the utility of highly variable nuclear markers, such as microsatellites, and ABC to test competing recolonization hypotheses. © 2015 John Wiley & Sons Ltd.

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

PubMed

Mandelker, Diana; Zhang, Liying; Kemel, Yelena; Stadler, Zsofia K; Joseph, Vijai; Zehir, Ahmet; Pradhan, Nisha; Arnold, Angela; Walsh, Michael F; Li, Yirong; Balakrishnan, Anoop R; Syed, Aijazuddin; Prasad, Meera; Nafa, Khedoudja; Carlo, Maria I; Cadoo, Karen A; Sheehan, Meg; Fleischut, Megan H; Salo-Mullen, Erin; Trottier, Magan; Lipkin, Steven M; Lincoln, Anne; Mukherjee, Semanti; Ravichandran, Vignesh; Cambria, Roy; Galle, Jesse; Abida, Wassim; Arcila, Marcia E; Benayed, Ryma; Shah, Ronak; Yu, Kenneth; Bajorin, Dean F; Coleman, Jonathan A; Leach, Steven D; Lowery, Maeve A; Garcia-Aguilar, Julio; Kantoff, Philip W; Sawyers, Charles L; Dickler, Maura N; Saltz, Leonard; Motzer, Robert J; O'Reilly, Eileen M; Scher, Howard I; Baselga, Jose; Klimstra, David S; Solit, David B; Hyman, David M; Berger, Michael F; Ladanyi, Marc; Robson, Mark E; Offit, Kenneth

2017-09-05

Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. clinicaltrials.gov Identifier: NCT01775072.

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

PubMed

Blum, Kenneth; Badgaiyan, Rajendra D; Agan, Gozde; Fratantonio, James; Simpatico, Thomas; Febo, Marcelo; Haberstick, Brett C; Smolen, Andrew; Gold, Mark S

The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARS PREDX ™), the first test to accurately predict one's genetic risk for RDS.

Cost sharing and hereditary cancer risk: predictors of willingness-to-pay for genetic testing.

PubMed

Matro, Jennifer M; Ruth, Karen J; Wong, Yu-Ning; McCully, Katen C; Rybak, Christina M; Meropol, Neal J; Hall, Michael J

2014-12-01

Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals' willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25-$2,000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤$200 vs. ≥$500). All statistical tests are two-sided (α = 0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p < 0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p < 0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care.

Cost sharing and hereditary cancer risk: Predictors of willingness-to-pay for genetic testing

PubMed Central

Matro, Jennifer M.; Ruth, Karen J.; Wong, Yu-Ning; McCully, Katen C.; Rybak, Christina M.; Meropol, Neal J.; Hall, Michael J.

2015-01-01

Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals’ willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25–$2000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤200 vs. ≥$500). All statistical tests are two-sided (α=0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p<0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p<0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care. PMID:24794065

Identification of Patients at Risk for Hereditary Colorectal Cancer

PubMed Central

Mishra, Nitin; Hall, Jason

2012-01-01

Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing. PMID:23730221

Ethical issues raised by genetic testing with oligonucleotide microarrays.

PubMed

Grody, Wayne W

2003-02-01

Because genes and alterations within them determine the identity, characteristics, and inheritance of every individual, the application of genetic science to humans has long been surrounded by apprehension, controversy, and real or perceived potential for abuse. Crude eugenics practices of the past now find a theoretical rebirth and transformation through the use of modern molecular genetic technologies for mutation detection, predictive and prenatal diagnosis, and, ultimately, gene replacement. The advent of oligonucleotide microarray analysis, in which hundreds or thousands of genes and mutations can be tested in parallel, offers tremendous promise for more accurate, sensitive, and efficient genetic testing. At the same time, however, this powerful technology dramatically increases the number and scope of ethical concerns accompanying each individual test request. This article considers the evolution and implications of these concerns, from the initial ordering of a microarray test by the physician to such issues as informed consent, privacy, confidentiality, clinical utility, discrimination, stigmatization, ethnic and population impact, and reimbursement.

DenguePredict: An Integrated Drug Repositioning Approach towards Drug Discovery for Dengue.

PubMed

Wang, QuanQiu; Xu, Rong

2015-01-01

Dengue is a viral disease of expanding global incidence without cures. Here we present a drug repositioning system (DenguePredict) leveraging upon a unique drug treatment database and vast amounts of disease- and drug-related data. We first constructed a large-scale genetic disease network with enriched dengue genetics data curated from biomedical literature. We applied a network-based ranking algorithm to find dengue-related diseases from the disease network. We then developed a novel algorithm to prioritize FDA-approved drugs from dengue-related diseases to treat dengue. When tested in a de-novo validation setting, DenguePredict found the only two drugs tested in clinical trials for treating dengue and ranked them highly: chloroquine ranked at top 0.96% and ivermectin at top 22.75%. We showed that drugs targeting immune systems and arachidonic acid metabolism-related apoptotic pathways might represent innovative drugs to treat dengue. In summary, DenguePredict, by combining comprehensive disease- and drug-related data and novel algorithms, may greatly facilitate drug discovery for dengue.

Are we ready for genetic testing for primary open-angle glaucoma?

PubMed

Khawaja, Anthony P; Viswanathan, Ananth C

2018-05-01

Following a dramatic reduction in the cost of genotyping technology in recent years, there have been significant advances in the understanding of the genetic basis of glaucoma. Glaucoma patients represent around a quarter of all outpatient activity in the UK hospital eye service and are a huge burden for the National Health Service. A potential benefit of genetic testing is personalised glaucoma management, allowing direction of our limited healthcare resources to the glaucoma patients who most need it. Our review aims to summarise recent discoveries in the field of glaucoma genetics and to discuss their potential clinical utility. While genome-wide association studies have now identified over ten genes associated with primary open-angle glaucoma (POAG), individually, variants in these genes are not predictive of POAG in populations. There are data suggesting some of these POAG variants are associated with conversion from ocular hypertension to POAG and visual field progression among POAG patients. However, these studies have not been replicated yet and such genetic testing is not currently justified in clinical care. In contrast, genetic testing for inherited early-onset disease in relatives of POAG patients with a known genetic mutation is of clear benefit; this can support either regular review to commence early treatment when the disease develops, or discharge from ophthalmology services of relatives who do not carry the mutation. Genetic testing for POAG at a population level is not currently justified.

Genetic Relations Among Procrastination, Impulsivity, and Goal-Management Ability: Implications for the Evolutionary Origin of Procrastination

PubMed Central

Gustavson, Daniel E.; Miyake, Akira; Hewitt, John K.; Friedman, Naomi P.

2014-01-01

Previous research has revealed a moderate positive correlation between procrastination and impulsivity. However, little is known about why these two constructs are related. This study used behavioral genetic methodology to test three predictions derived from an evolutionary account that postulates that procrastination arose as a by-product of impulsivity (Steel, 2010): (a) Procrastination is heritable; (b) the two traits share considerable genetic variation; and (c) goal-management ability is an important component of this shared variation. These predictions were confirmed. First, both procrastination and impulsivity were moderately heritable (46% and 49%, respectively). Second, although the two traits were separable at the phenotypic level (r=.65), they were not separable at the genetic level (rg=1.0). Finally, variation in goal-management ability accounted for much of this shared genetic variation. These results suggest that procrastination and impulsivity are linked primarily through genetic influences on the ability to use their high-priority goals effectively to regulate their action. PMID:24705635

Against Genetic Tests for Athletic Talent: The Primacy of the Phenotype.

PubMed

Loland, Sigmund

2015-09-01

New insights into the genetics of sport performance lead to new areas of application. One area is the use of genetic tests to identify athletic talent. Athletic performances involve a high number of complex phenotypical traits. Based on the ACCE model (review of Analytic and Clinical validity, Clinical utility, and Ethical, legal and social implications), a critique is offered of the lack of validity and predictive power of genetic tests for talent. Based on the ideal of children's right to an open future, a moral argument is given against such tests on children and young athletes. A possible role of genetic tests in sport is proposed in terms of identifying predisposition for injury. In meeting ACCE requirements, such tests could improve individualised injury prevention and increase athlete health. More generally, limitations of science are discussed in the identification of talent and in the understanding of complex human performance phenotypes. An alternative approach to talent identification is proposed in terms of ethically sensitive, systematic and evidence-based holistic observation over time of relevant phenotypical traits by experienced observers. Talent identification in sport should be based on the primacy of the phenotype.

Let the consumer decide? The regulation of commercial genetic testing.

PubMed

Levitt, D M

2001-12-01

The development of predictive genetic tests provides a new area where consumers can gain knowledge of their health status and commercial opportunities. "Over-the-counter" or mail order genetic tests are most likely to provide information on carrier status or the risk of developing a multifactorial disease. The paper considers the social and ethical implications of individuals purchasing genetic tests and whether genetic information is different from other types of health information which individuals can obtain for themselves. The discussion is illustrated by findings from a questionnaire survey of university students as potential consumers. Topics covered included what health tests they had already used, expectations of genetic tests, willingness to pay, who should have access to the results and whether there need to be restrictions on such tests. SAMPLE-Six hundred and fifteen first-year students in the universities of Leuven, Cardiff, Central Lancashire, Vienna and Nijmegen studying either medicine or a non-science subject. Students were enthusiastic about genetic tests and had high expectations of their accuracy and usefulness but most thought they should be available through the health service and a minority thought that some tests, for example for sex selection, should not be available at all. There were few differences in responses by sex or subject of study but some by country. The paper also considers ethical and social issues outside the scope of a questionnaire survey of this type. To address some of these issues the sale of genetic tests to individuals can be made subject to ethical guidelines or codes of practice, for example to protect vulnerable groups, but there are fundamental social and ethical questions which such guidelines cannot address.

Predictive Genetic Testing and Alternatives to Face to Face Results Disclosure: A Retrospective Review of Patients Preference for Alternative Modes of BRCA 1 and 2 Results Disclosure in the Republic of Ireland.

PubMed

O'Shea, Rosie; Meany, Marie; Carroll, Cliona; Cody, Nuala; Healy, David; Green, Andrew; Lynch, Sally Ann

2016-06-01

The traditional model of providing cancer predictive testing services is changing. Many genetic centres are now offering a choice to patients in how they receive their results instead of the typical face-to-face disclosure. In view of this shift in practice and the increasing demand on the ROI cancer predictive testing service, a 2 year retrospective study on patient preference in how to receive a Breast Cancer (BRCA) predictive result was carried out. Results showed that 71.7 % of respondents would have liked to have the option of obtaining their results by telephone or by letter. However, when asked about their actual experience of BRCA predictive results disclosure 40.6 % did still value the face-to-face contact, while 44.9 % would still have preferred to receive results by either post or telephone. No significant difference was found between males and females (p > 0.05) and those who tested negative or positive for the BRCA mutation (p > 0.05) in wanting a choice in how their results were disclosed. While the majority expressed a wish to have a choice in how to receive their results, it is important not to underestimate the value of a face-to-face encounter in these circumstances.

TANTAMOUNT TO FRAUD?: EXPLORING NON-DISCLOSURE OF GENETIC INFORMATION IN LIFE INSURANCE APPLICATIONS AS GROUNDS FOR POLICY RESCISSION.

PubMed

Prince, Anya E R

2016-01-01

Many genetic counselors recommend that individuals secure desired insurance policies, such as life insurance, prior to undergoing predictive genetic testing. It has been argued, however, that this practice is "tantamount to fraud" and that failure to disclose genetic test results, or conspiring to secure a policy before testing, opens an individual up to legal recourse. This debate traps affected individuals in a Catch-22. If they apply for life insurance and disclose a genetic test result, they may be denied. If they apply without disclosing the information, they may have committed fraud. The consequences of life insurance fraud are significant: If fraud is found on an application, a life insurer can rescind the policy, in some cases even after the individual has passed away. Such a rescission could leave family members or beneficiaries without the benefits of the life insurance policy payment after the individual's death and place them in in economic difficulty. Although it is clear that lying in response to a direct question about genetic testing would be tantamount to fraud, few, if any, life insurance applications currently include broad questions about genetic testing. This paper investigates whether non-disclosure of unasked for genetic information constitutes fraud and explores varying types of insurance questions that could conceivably be interpreted as seeking genetic information. Life insurance applicants generally have no duty to disclose unasked for information, including genetic information, on an application. However, given the complexities of genetic information, individuals may be exposed to fraud and rescission of their life insurance policy despite honest attempts to truthfully and completely answer all application questions.

Use of genetic programming, logistic regression, and artificial neural nets to predict readmission after coronary artery bypass surgery.

PubMed

Engoren, Milo; Habib, Robert H; Dooner, John J; Schwann, Thomas A

2013-08-01

As many as 14 % of patients undergoing coronary artery bypass surgery are readmitted within 30 days. Readmission is usually the result of morbidity and may lead to death. The purpose of this study is to develop and compare statistical and genetic programming models to predict readmission. Patients were divided into separate Construction and Validation populations. Using 88 variables, logistic regression, genetic programs, and artificial neural nets were used to develop predictive models. Models were first constructed and tested on the Construction populations, then validated on the Validation population. Areas under the receiver operator characteristic curves (AU ROC) were used to compare the models. Two hundred and two patients (7.6 %) in the 2,644 patient Construction group and 216 (8.0 %) of the 2,711 patient Validation group were re-admitted within 30 days of CABG surgery. Logistic regression predicted readmission with AU ROC = .675 ± .021 in the Construction group. Genetic programs significantly improved the accuracy, AU ROC = .767 ± .001, p < .001). Artificial neural nets were less accurate with AU ROC = 0.597 ± .001 in the Construction group. Predictive accuracy of all three techniques fell in the Validation group. However, the accuracy of genetic programming (AU ROC = .654 ± .001) was still trivially but statistically non-significantly better than that of the logistic regression (AU ROC = .644 ± .020, p = .61). Genetic programming and logistic regression provide alternative methods to predict readmission that are similarly accurate.

Facial averageness and genetic quality: Testing heritability, genetic correlation with attractiveness, and the paternal age effect.

PubMed

Lee, Anthony J; Mitchem, Dorian G; Wright, Margaret J; Martin, Nicholas G; Keller, Matthew C; Zietsch, Brendan P

2016-01-01

Popular theory suggests that facial averageness is preferred in a partner for genetic benefits to offspring. However, whether facial averageness is associated with genetic quality is yet to be established. Here, we computed an objective measure of facial averageness for a large sample ( N = 1,823) of identical and nonidentical twins and their siblings to test two predictions from the theory that facial averageness reflects genetic quality. First, we use biometrical modelling to estimate the heritability of facial averageness, which is necessary if it reflects genetic quality. We also test for a genetic association between facial averageness and facial attractiveness. Second, we assess whether paternal age at conception (a proxy of mutation load) is associated with facial averageness and facial attractiveness. Our findings are mixed with respect to our hypotheses. While we found that facial averageness does have a genetic component, and a significant phenotypic correlation exists between facial averageness and attractiveness, we did not find a genetic correlation between facial averageness and attractiveness (therefore, we cannot say that the genes that affect facial averageness also affect facial attractiveness) and paternal age at conception was not negatively associated with facial averageness. These findings support some of the previously untested assumptions of the 'genetic benefits' account of facial averageness, but cast doubt on others.

The Canadian Pharmacogenomics Network for Drug Safety: a model for safety pharmacology.

PubMed

Ross, Colin J D; Visscher, Henk; Sistonen, Johanna; Brunham, Liam R; Pussegoda, Kusala; Loo, Tenneille T; Rieder, Michael J; Koren, Gideon; Carleton, Bruce C; Hayden, Michael R

2010-07-01

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death in the developed world, and the direct medical costs of ADRs exceed $100 billion annually in the United States alone. Pharmacogenomics research seeks to identify genetic factors that are responsible for individual differences in drug efficacy and susceptibility to ADRs. This has led to several genetic tests that are currently being used to provide clinical recommendations. The Canadian Pharmacogenomics Network for Drug Safety is a nation-wide effort established in Canada to identify novel predictive genomic markers of severe ADRs in children and adults. A surveillance network has been established in 17 of Canada's major hospitals to identify patients experiencing specific ADRs and to collect biological samples and relevant clinical history for genetic association studies. To identify ADR-associated genetic markers that could be incorporated into predictive tests that will reduce the occurrence of serious ADRs, high-throughput genomic analyses are conducted with samples from patients that have suffered serious ADRs and matched control patients. ADRs represent a significant unmet medical problem with significant morbidity and mortality, and Canadian Pharmacogenomics Network for Drug Safety is a nation-wide network in Canada that seeks to identify genetic factors responsible for interindividual differences in susceptibility to serious ADRs. Active ADR surveillance is necessary to identify and recruit patients who suffer from serious ADRs. National and international collaborations are required to recruit sufficient patients for these studies. Several pharmacogenomics tests are currently in clinical use to provide dosing recommendations, and the number of pharmacogenomics tests is expected to significantly increase in the future.

Characteristics associated with genetic counseling referral and BRCA1/2 testing among women in a large integrated health system.

PubMed

Bellcross, Cecelia A; Peipins, Lucy A; McCarty, Frances A; Rodriguez, Juan L; Hawkins, Nikki A; Hensley Alford, Sharon; Leadbetter, Steven

2015-01-01

Evidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing. An ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate). Among the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0-9.6) to report genetic counseling referral. In a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing.

Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.

PubMed

Lee, Jin Hwa; Cho, Michael H; McDonald, Merry-Lynn N; Hersh, Craig P; Castaldi, Peter J; Crapo, James D; Wan, Emily S; Dy, Jennifer G; Chang, Yale; Regan, Elizabeth A; Hardin, Megan; DeMeo, Dawn L; Silverman, Edwin K

2014-10-01

Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1). Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD 1 and smoking control subjects. K-means clustering of GOLD 1 subjects identified putative "near-normal", "airway-predominant", "emphysema-predominant" and "lowest FEV1% predicted" subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1% predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects. Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Social and genetic structure of paper wasp cofoundress associations: tests of reproductive skew models.

PubMed

Field, J; Solís, C R; Queller, D C; Strassmann, J E

1998-06-01

Recent models postulate that the members of a social group assess their ecological and social environments and agree a "social contract" of reproductive partitioning (skew). We tested social contracts theory by using DNA microsatellites to measure skew in 24 cofoundress associations of paper wasps, Polistes bellicosus. In contrast to theoretical predictions, there was little variation in cofoundress relatedness, and relatedness either did not predict skew or was negatively correlated with it; the dominant/subordinate size ratio, assumed to reflect relative fighting ability, did not predict skew; and high skew was associated with decreased aggression by the rank 2 subordinate toward the dominant. High skew was associated with increased group size. A difficulty with measuring skew in real systems is the frequent changes in group composition that commonly occur in social animals. In P. bellicosus, 61% of egg layers and an unknown number of non-egg layers were absent by the time nests were collected. The social contracts models provide an attractive general framework linking genetics, ecology, and behavior, but there have been few direct tests of their predictions. We question assumptions underlying the models and suggest directions for future research.

Comparative Analysis of Soft Computing Models in Prediction of Bending Rigidity of Cotton Woven Fabrics

NASA Astrophysics Data System (ADS)

Guruprasad, R.; Behera, B. K.

2015-10-01

Quantitative prediction of fabric mechanical properties is an essential requirement for design engineering of textile and apparel products. In this work, the possibility of prediction of bending rigidity of cotton woven fabrics has been explored with the application of Artificial Neural Network (ANN) and two hybrid methodologies, namely Neuro-genetic modeling and Adaptive Neuro-Fuzzy Inference System (ANFIS) modeling. For this purpose, a set of cotton woven grey fabrics was desized, scoured and relaxed. The fabrics were then conditioned and tested for bending properties. With the database thus created, a neural network model was first developed using back propagation as the learning algorithm. The second model was developed by applying a hybrid learning strategy, in which genetic algorithm was first used as a learning algorithm to optimize the number of neurons and connection weights of the neural network. The Genetic algorithm optimized network structure was further allowed to learn using back propagation algorithm. In the third model, an ANFIS modeling approach was attempted to map the input-output data. The prediction performances of the models were compared and a sensitivity analysis was reported. The results show that the prediction by neuro-genetic and ANFIS models were better in comparison with that of back propagation neural network model.

Genetic Diagnosis and Testing in Clinical Practice

PubMed Central

McPherson, Elizabeth

2006-01-01

Genetic testing is defined as “the analysis of human DNA, RNA, chromosomes, proteins and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes or karyotypes for clinical purposes.” This article focuses on diagnostic and predictive genetic testing. The latter includes presymptomatic testing, which identifies individuals who are expected to become ill in the future and predisposition testing, which identifies those who are at increased risk of becoming ill. Decisions regarding genetic testing must be based not only on the analytic accuracy, availability and cost of the test, but on the clinical utility as well, including the sensitivity, specificity and interpretability of results. Clinical information, including the medical and family history and the findings of the physical examination, is vital for the selection of appropriate diagnostic tests, as well as the interpretation of the results. Presymptomatic genetic testing is a very personal choice that should only be made after the patient has had sufficient counseling to develop an understanding of the risks and benefits of the test and is able to make an informed decision. The same principle applies to predisposition testing; however, additional factors, such as the probability of a positive result, the likelihood that the disease will actually develop in those with positive results, the effect on the management of the index patient, the effects on family members, the risk of false reassurance if the result is negative or the potential for loss of hope if it is positive, all contribute to the assessment of risk versus benefit. Clinical evaluation and counseling of the patient who is at risk for a genetic disorder are labor intensive but essential for the selection and interpretation of genetic tests. PMID:16809405

The Genetic Interpretation of Area under the ROC Curve in Genomic Profiling

PubMed Central

Wray, Naomi R.; Yang, Jian; Goddard, Michael E.; Visscher, Peter M.

2010-01-01

Genome-wide association studies in human populations have facilitated the creation of genomic profiles which combine the effects of many associated genetic variants to predict risk of disease. The area under the receiver operator characteristic (ROC) curve is a well established measure for determining the efficacy of tests in correctly classifying diseased and non-diseased individuals. We use quantitative genetics theory to provide insight into the genetic interpretation of the area under the ROC curve (AUC) when the test classifier is a predictor of genetic risk. Even when the proportion of genetic variance explained by the test is 100%, there is a maximum value for AUC that depends on the genetic epidemiology of the disease, i.e. either the sibling recurrence risk or heritability and disease prevalence. We derive an equation relating maximum AUC to heritability and disease prevalence. The expression can be reversed to calculate the proportion of genetic variance explained given AUC, disease prevalence, and heritability. We use published estimates of disease prevalence and sibling recurrence risk for 17 complex genetic diseases to calculate the proportion of genetic variance that a test must explain to achieve AUC = 0.75; this varied from 0.10 to 0.74. We provide a genetic interpretation of AUC for use with predictors of genetic risk based on genomic profiles. We provide a strategy to estimate proportion of genetic variance explained on the liability scale from estimates of AUC, disease prevalence, and heritability (or sibling recurrence risk) available as an online calculator. PMID:20195508

Eugenics and genetic testing.

PubMed

Holtzman, N A

1998-01-01

Pressures to lower health-care costs remain an important stimulus to eugenic approaches. Prenatal diagnosis followed by abortion of affected fetuses has replaced sterilization as the major eugenic technique. Voluntary acceptance has replaced coercion, but subtle pressures undermine personal autonomy. The failure of the old eugenics to accurately predict who will have affected offspring virtually disappears when prenatal diagnosis is used to predict Mendelian disorders. However, when prenatal diagnosis is used to detect inherited susceptibilities to adult-onset, common, complex disorders, considerable uncertainty is inherent in the prediction. Intolerance and the resurgence of genetic determinism are current pressures for a eugenic approach. The increasing use of carrier screening (to identify those at risk of having affected offspring) and of prenatal diagnosis could itself generate intolerance for those who refuse the procedures. Genetic determinism deflects society from social action that would reduce the burden of disease far more than even the maximum use of eugenics.

Validation of test-day models for genetic evaluation of dairy goats in Norway.

PubMed

Andonov, S; Ødegård, J; Boman, I A; Svendsen, M; Holme, I J; Adnøy, T; Vukovic, V; Klemetsdal, G

2007-10-01

Test-day data for daily milk yield and fat, protein, and lactose content were sampled from the years 1988 to 2003 in 17 flocks belonging to 2 genetically well-tied buck circles. In total, records from 2,111 to 2,215 goats for content traits and 2,371 goats for daily milk yield were included in the analysis, averaging 2.6 and 4.8 observations per goat for the 2 groups of traits, respectively. The data were analyzed by using 4 test-day models with different modeling of fixed effects. Model [0] (the reference model) contained a fixed effect of year-season of kidding with regression on Ali-Schaeffer polynomials nested within the year-season classes, and a random effect of flock test-day. In model [1], the lactation curve effect from model [0] was replaced by a fixed effect of days in milk (in 3-d periods), the same for all year-seasons of kidding. Models [2] and [3] were obtained from model [1] by removing the fixed year-season of kidding effect and considering the flock test-day effect as either fixed or random, respectively. The models were compared by using 2 criteria: mean-squared error of prediction and a test of bias affecting the genetic trend. The first criterion indicated a preference for model [3], whereas the second criterion preferred model [1]. Mean-squared error of prediction is based on model fit, whereas the second criterion tests the ability of the model to produce unbiased genetic evaluation (i.e., its capability of separating environmental and genetic time trends). Thus, a fixed structure with year (year, year-season, or possibly flock-year) was indicated to appropriately separate time trends. Heritability estimates for daily milk yield and milk content were 0.26 and 0.24 to 0.27, respectively.

Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

PubMed Central

Savić Pavićević, Dušanka; Miladinović, Jelena; Brkušanin, Miloš; Šviković, Saša; Djurica, Svetlana; Brajušković, Goran; Romac, Stanka

2013-01-01

Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling. PMID:23586035

Validity of Models for Predicting BRCA1 and BRCA2 Mutations

PubMed Central

Parmigiani, Giovanni; Chen, Sining; Iversen, Edwin S.; Friebel, Tara M.; Finkelstein, Dianne M.; Anton-Culver, Hoda; Ziogas, Argyrios; Weber, Barbara L.; Eisen, Andrea; Malone, Kathleen E.; Daling, Janet R.; Hsu, Li; Ostrander, Elaine A.; Peterson, Leif E.; Schildkraut, Joellen M.; Isaacs, Claudine; Corio, Camille; Leondaridis, Leoni; Tomlinson, Gail; Amos, Christopher I.; Strong, Louise C.; Berry, Donald A.; Weitzel, Jeffrey N.; Sand, Sharon; Dutson, Debra; Kerber, Rich; Peshkin, Beth N.; Euhus, David M.

2008-01-01

Background Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood. Objective To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University. Design Cross-sectional validation study, using model predictions and BRCA1 or BRCA2 mutation status of patients different from those used to develop the models. Setting Multicenter study across Cancer Genetics Network participating centers. Patients 3 population-based samples of participants in research studies and 8 samples from genetic counseling clinics. Measurements Discrimination between individuals testing positive for a mutation in BRCA1 or BRCA2 from those testing negative, as measured by the c-statistic, and sensitivity and specificity of model predictions. Results The 7 models differ in their predictions. The better-performing models have a c-statistic around 80%. BRCAPRO has the largest c-statistic overall and in all but 2 patient subgroups, although the margin over other models is narrow in many strata. Outside of high-risk populations, all models have high false-negative and false-positive rates across a range of probability thresholds used to refer for mutation testing. Limitation Three recently published models were not included. Conclusions All models identify women who probably carry a deleterious mutation of BRCA1 or BRCA2 with adequate discrimination to support individualized genetic counseling, although discrimination varies across models and populations. PMID:17909205

Underestimation of Risk of a BRCA1 or BRCA2 Mutation in Women With High-Grade Serous Ovarian Cancer by BRCAPRO: A Multi-Institution Study

PubMed Central

Daniels, Molly S.; Babb, Sheri A.; King, Robin H.; Urbauer, Diana L.; Batte, Brittany A.L.; Brandt, Amanda C.; Amos, Christopher I.; Buchanan, Adam H.; Mutch, David G.; Lu, Karen H.

2014-01-01

Purpose Identification of the 10% to 15% of patients with ovarian cancer who have germline BRCA1 or BRCA2 mutations is important for management of both patients and relatives. The BRCAPRO model, which estimates mutation likelihood based on personal and family cancer history, can inform genetic testing decisions. This study's purpose was to assess the accuracy of BRCAPRO in women with ovarian cancer. Methods BRCAPRO scores were calculated for 589 patients with ovarian cancer referred for genetic counseling at three institutions. Observed mutations were compared with those predicted by BRCAPRO. Analysis of variance was used to assess factors impacting BRCAPRO accuracy. Results One hundred eighty (31%) of 589 patients with ovarian cancer tested positive. At BRCAPRO scores less than 40%, more mutations were observed than expected (93 mutations observed v 34.1 mutations expected; P < .001). If patients with BRCAPRO scores less than 10% had not been tested, 51 (28%) of 180 mutations would have been missed. BRCAPRO underestimated the risk for high-grade serous ovarian cancers but overestimated the risk for other histologies (P < .001), underestimation increased as age at diagnosis decreased (P = .02), and model performance varied by institution (P = .02). Conclusion Patients with ovarian cancer classified as low risk by BRCAPRO are more likely to test positive than predicted. The risk of a mutation in patients with low BRCAPRO scores is high enough to warrant genetic testing. This study demonstrates that assessment of family history by a validated model cannot effectively target testing to a high-risk ovarian cancer patient population, which strongly supports the recommendation to offer BRCA1/BRCA2 genetic testing to all patients with high-grade serous ovarian cancer regardless of family history. PMID:24638001

Genetic Counselling for Predictive Testing in Huntington's Disease in One Centre since 1993. Gender-Specific Aspects of Decision-Making.

PubMed

Arning, Larissa; Witt, Constantin N; Epplen, Jörg T; Stemmler, Susanne

2015-01-01

The discovery of the mutation causing Huntington's disease (HD) in 1993 allowed direct mutation analysis and predictive testing to identify currently unaffected carriers with a sensitivity and specificity of virtually 100%. The present study was designed to comprehensively profile the participants who sought predictive testing for HD between 1993 and 2009 in our Huntington centre. Using a retrospective design, we analysed the written documentation of the counselling sessions for all referrals for predictive mutation testing in this time span. Six hundred sixty-three individuals at risk for HD requested predictive testing. Roughly half (n = 333) completed the protocol and received their test result. In general our findings are in accordance with other reports: most participants share an a priori risk of 50% (91.1%); more females request testing (58.5%); and those who ask for the result are mostly in their 30 s (mean = 35.1 years). Of those at 50% or 25% prior risks, 47.4% and 22.7%, respectively, tested positive in accordance with the respective risk of inheriting HD. Generally, more participants with an affected mother than father sought genetic testing (52.5% versus 47.5%). Interestingly, this difference was especially evident in the group of females who finally withdrew from testing (59.1%, p = 0.040). Men, in particular those who decided in favour of the test, were more often accompanied by their partner in the pre-test counselling session than vice versa (67.9% versus 44.7%, p = 0.003). On the other hand, significantly more men who were being tested did not have a companion in the pre-test session as compared with men who decided against the test (40.0% versus 25.7%, p = 0.012). During the first four years of predictive testing (1993–1996) more participants completed the protocol and received their test result as in later years. Yet, in this early time span significantly fewer females finally decided in favour of the test (48.4%, p = 0.005). These findings are discussed longitudinally and in the context of the experience in other centres. We present new gender-specific aspects of decision-making for predictive HD tests.

Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer.

PubMed

Thirthagiri, E; Lee, S Y; Kang, P; Lee, D S; Toh, G T; Selamat, S; Yoon, S-Y; Taib, N A Mohd; Thong, M K; Yip, C H; Teo, S H

2008-01-01

The cost of genetic testing and the limited knowledge about the BRCA1 and BRCA2 genes in different ethnic groups has limited its availability in medium- and low-resource countries, including Malaysia. In addition, the applicability of many risk-assessment tools, such as the Manchester Scoring System and BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) which were developed based on mutation rates observed primarily in Caucasian populations using data from multiplex families, and in populations where the rate of breast cancer is higher, has not been widely tested in Asia or in Asians living elsewhere. Here, we report the results of genetic testing for mutations in the BRCA1 or BRCA2 genes in a series of families with breast cancer in the multi-ethnic population (Malay, Chinese and Indian) of Malaysia. A total of 187 breast cancer patients with either early-onset breast cancer (at age

The relative importance of genetic and nongenetic inheritance in relation to trait plasticity in Callosobruchus maculatus.

PubMed

Hallsson, L R; Chenoweth, S F; Bonduriansky, R

2012-12-01

A trait's response to natural selection will reflect the nature of the inheritance mechanisms that mediate the transmission of variation across generations. The relative importance of genetic and nongenetic mechanisms of inheritance is predicted to be related to the degree of trait plasticity, with nongenetic inheritance playing a greater role in the cross-generational transmission of more plastic traits. However, this prediction has never been tested. We investigated the influence of genetic effects and nongenetic parental effects in two morphological traits differing in degree of plasticity by manipulating larval diet quality within a cross-generational split-brood experiment using the seed beetle Callososbuchus maculatus. In line with predictions, we found that the more plastic trait (elytron length) is strongly influenced by both maternal and paternal effects whereas genetic variance is undetectable. In contrast, the less plastic trait (first abdominal sternite length) is not influenced by parental effects but exhibits abundant genetic variance. Our findings support the hypothesis that environment-dependent parental effects may play a particularly important role in highly plastic traits and thereby affect the evolutionary response of such traits. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

Education, Genetic Ancestry, and Blood Pressure in African Americans and Whites

PubMed Central

Gravlee, Clarence C.; Mulligan, Connie J.

2012-01-01

Objectives. We assessed the relative roles of education and genetic ancestry in predicting blood pressure (BP) within African Americans and explored the association between education and BP across racial groups. Methods. We used t tests and linear regressions to examine the associations of genetic ancestry, estimated from a genomewide set of autosomal markers, and education with BP variation among African Americans in the Family Blood Pressure Program. We also performed linear regressions in self-identified African Americans and Whites to explore the association of education with BP across racial groups. Results. Education, but not genetic ancestry, significantly predicted BP variation in the African American subsample (b = −0.51 mm Hg per year additional education; P = .001). Although education was inversely associated with BP in the total population, within-group analyses showed that education remained a significant predictor of BP only among the African Americans. We found a significant interaction (b = 3.20; P = .006) between education and self-identified race in predicting BP. Conclusions. Racial disparities in BP may be better explained by differences in education than by genetic ancestry. Future studies of ancestry and disease should include measures of the social environment. PMID:22698014

Education, genetic ancestry, and blood pressure in African Americans and Whites.

PubMed

Non, Amy L; Gravlee, Clarence C; Mulligan, Connie J

2012-08-01

We assessed the relative roles of education and genetic ancestry in predicting blood pressure (BP) within African Americans and explored the association between education and BP across racial groups. We used t tests and linear regressions to examine the associations of genetic ancestry, estimated from a genomewide set of autosomal markers, and education with BP variation among African Americans in the Family Blood Pressure Program. We also performed linear regressions in self-identified African Americans and Whites to explore the association of education with BP across racial groups. Education, but not genetic ancestry, significantly predicted BP variation in the African American subsample (b=-0.51 mm Hg per year additional education; P=.001). Although education was inversely associated with BP in the total population, within-group analyses showed that education remained a significant predictor of BP only among the African Americans. We found a significant interaction (b=3.20; P=.006) between education and self-identified race in predicting BP. Racial disparities in BP may be better explained by differences in education than by genetic ancestry. Future studies of ancestry and disease should include measures of the social environment.

How does genetic risk information for Lynch syndrome translate to risk management behaviours?

PubMed

Steel, Emma; Robbins, Andrew; Jenkins, Mark; Flander, Louisa; Gaff, Clara; Keogh, Louise

2017-01-01

There is limited research on why some individuals who have undergone predictive genetic testing for Lynch syndrome do not adhere to screening recommendations. This study aimed to explore qualitatively how Lynch syndrome non-carriers and carriers translate genetic risk information and advice to decisions about risk managment behaviours in the Australian healthcare system. Participants of the Australasian Colorectal Cancer Family Registry who had undergone predictive genetic testing for Lynch syndrome were interviewed on their risk management behaviours. Transcripts were analysed thematically using a comparative coding analysis. Thirty-three people were interviewed. Of the non-carriers ( n  = 16), 2 reported having apparently unnecessary colonoscopies, and 6 were unsure about what population-based colorectal cancer screening entails. Of the carriers ( n  = 17), 2 reported they had not had regular colonoscopies, and spoke about their discomfort with the screening process and a lack of faith in the procedure's ability to reduce their risk of developing colorectal cancer. Of the female carriers ( n  = 9), 2 could not recall being informed about the associated risk of gynaecological cancers. Non-carriers and female carriers of Lynch syndrome could benefit from further clarity and advice about appropriate risk management options. For those carriers who did not adhere to colonoscopy screening, a lack of faith in both genetic test results and screening were evident. It is essential that consistent advice is offered to both carriers and non-carriers of Lynch syndrome.

Linear and Poisson models for genetic evaluation of tick resistance in cross-bred Hereford x Nellore cattle.

PubMed

Ayres, D R; Pereira, R J; Boligon, A A; Silva, F F; Schenkel, F S; Roso, V M; Albuquerque, L G

2013-12-01

Cattle resistance to ticks is measured by the number of ticks infesting the animal. The model used for the genetic analysis of cattle resistance to ticks frequently requires logarithmic transformation of the observations. The objective of this study was to evaluate the predictive ability and goodness of fit of different models for the analysis of this trait in cross-bred Hereford x Nellore cattle. Three models were tested: a linear model using logarithmic transformation of the observations (MLOG); a linear model without transformation of the observations (MLIN); and a generalized linear Poisson model with residual term (MPOI). All models included the classificatory effects of contemporary group and genetic group and the covariates age of animal at the time of recording and individual heterozygosis, as well as additive genetic effects as random effects. Heritability estimates were 0.08 ± 0.02, 0.10 ± 0.02 and 0.14 ± 0.04 for MLIN, MLOG and MPOI models, respectively. The model fit quality, verified by deviance information criterion (DIC) and residual mean square, indicated fit superiority of MPOI model. The predictive ability of the models was compared by validation test in independent sample. The MPOI model was slightly superior in terms of goodness of fit and predictive ability, whereas the correlations between observed and predicted tick counts were practically the same for all models. A higher rank correlation between breeding values was observed between models MLOG and MPOI. Poisson model can be used for the selection of tick-resistant animals. © 2013 Blackwell Verlag GmbH.

Short communication: Genetic lag represents commercial herd genetic merit more accurately than the 4-path selection model.

PubMed

Dechow, C D; Rogers, G W

2018-05-01

Expectation of genetic merit in commercial dairy herds is routinely estimated using a 4-path genetic selection model that was derived for a closed population, but commercial herds using artificial insemination sires are not closed. The 4-path model also predicts a higher rate of genetic progress in elite herds that provide artificial insemination sires than in commercial herds that use such sires, which counters other theoretical assumptions and observations of realized genetic responses. The aim of this work is to clarify whether genetic merit in commercial herds is more accurately reflected under the assumptions of the 4-path genetic response formula or by a genetic lag formula. We demonstrate by tracing the transmission of genetic merit from parents to offspring that the rate of genetic progress in commercial dairy farms is expected to be the same as that in the genetic nucleus. The lag in genetic merit between the nucleus and commercial farms is a function of sire and dam generation interval, the rate of genetic progress in elite artificial insemination herds, and genetic merit of sires and dams. To predict how strategies such as the use of young versus daughter-proven sires, culling heifers following genomic testing, or selective use of sexed semen will alter genetic merit in commercial herds, genetic merit expectations for commercial herds should be modeled using genetic lag expectations. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

In situ genetic association for serotiny, a fire-related trait, in Mediterranean maritime pine (Pinus pinaster).

PubMed

Budde, Katharina B; Heuertz, Myriam; Hernández-Serrano, Ana; Pausas, Juli G; Vendramin, Giovanni G; Verdú, Miguel; González-Martínez, Santiago C

2014-01-01

Wildfire is a major ecological driver of plant evolution. Understanding the genetic basis of plant adaptation to wildfire is crucial, because impending climate change will involve fire regime changes worldwide. We studied the molecular genetic basis of serotiny, a fire-related trait, in Mediterranean maritime pine using association genetics. A single nucleotide polymorphism (SNP) set was used to identify genotype : phenotype associations in situ in an unstructured natural population of maritime pine (eastern Iberian Peninsula) under a mixed-effects model framework. RR-BLUP was used to build predictive models for serotiny in this region. Model prediction power outside the focal region was tested using independent range-wide serotiny data. Seventeen SNPs were potentially associated with serotiny, explaining approximately 29% of the trait phenotypic variation in the eastern Iberian Peninsula. Similar prediction power was found for nearby geographical regions from the same maternal lineage, but not for other genetic lineages. Association genetics for ecologically relevant traits evaluated in situ is an attractive approach for forest trees provided that traits are under strong genetic control and populations are unstructured, with large phenotypic variability. This will help to extend the research focus to ecological keystone non-model species in their natural environments, where polymorphisms acquired their adaptive value. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Awareness, knowledge, perceptions, and attitudes towards genetic testing for cancer risk among ethnic minority groups: a systematic review.

PubMed

Hann, Katie E J; Freeman, Madeleine; Fraser, Lindsay; Waller, Jo; Sanderson, Saskia C; Rahman, Belinda; Side, Lucy; Gessler, Sue; Lanceley, Anne

2017-05-25

Genetic testing for risk of hereditary cancer can help patients to make important decisions about prevention or early detection. US and UK studies show that people from ethnic minority groups are less likely to receive genetic testing. It is important to understand various groups' awareness of genetic testing and its acceptability to avoid further disparities in health care. This review aims to identify and detail awareness, knowledge, perceptions, and attitudes towards genetic counselling/testing for cancer risk prediction in ethnic minority groups. A search was carried out in PsycInfo, CINAHL, Embase and MEDLINE. Search terms referred to ethnicity, genetic testing/counselling, cancer, awareness, knowledge, attitudes, and perceptions. Quantitative and qualitative studies, written in English, and published between 2000 and 2015, were included. Forty-one studies were selected for review: 39 from the US, and two from Australia. Results revealed low awareness and knowledge of genetic counselling/testing for cancer susceptibility amongst ethnic minority groups including African Americans, Asian Americans, and Hispanics. Attitudes towards genetic testing were generally positive; perceived benefits included positive implications for personal health and being able to inform family. However, negative attitudes were also evident, particularly the anticipated emotional impact of test results, and concerns about confidentiality, stigma, and discrimination. Chinese Australian groups were less studied, but of interest was a finding from qualitative research indicating that different views of who close family members are could impact on reported family history of cancer, which could in turn impact a risk assessment. Interventions are needed to increase awareness and knowledge of genetic testing for cancer risk and to reduce the perceived stigma and taboo surrounding the topic of cancer in ethnic minority groups. More detailed research is needed in countries other than the US and across a broader spectrum of ethnic minority groups to develop effective culturally sensitive approaches for cancer prevention.

Impact of literacy and numeracy on motivation for behavior change after diabetes genetic risk testing.

PubMed

Vassy, Jason L; O'Brien, Kelsey E; Waxler, Jessica L; Park, Elyse R; Delahanty, Linda M; Florez, Jose C; Meigs, James B; Grant, Richard W

2012-01-01

Type 2 diabetes genetic risk testing might motivate at-risk patients to adopt diabetes prevention behaviors. However, the influence of literacy and numeracy on patient response to diabetes genetic risk is unknown. The authors investigated the association of health literacy, genetic literacy, and health numeracy with patient responses to diabetes genetic risk. and Measurements Overweight patients at high phenotypic risk for type 2 diabetes were recruited for a clinical trial of diabetes genetic risk testing. At baseline, participants predicted how their motivation for lifestyle modification to prevent diabetes might change in response to hypothetical scenarios of receiving "high" and "low" genetic risk results. Responses were analyzed according to participants' health literacy, genetic literacy, and health numeracy. Two-thirds (67%) of participants (n = 175) reported very high motivation to prevent diabetes. Despite high health literacy (92% at high school level), many participants had limited health numeracy (30%) and genetic literacy (38%). Almost all (98%) reported that high-risk genetic results would increase their motivation for lifestyle modification. In contrast, response to low-risk genetic results varied. Higher levels of health literacy (P = 0.04), genetic literacy (P = 0.02), and health numeracy (P = 0.02) were associated with an anticipated decrease in motivation for lifestyle modification in response to low-risk results. While patients reported that high-risk genetic results would motivate them to adopt healthy lifestyle changes, response to low-risk results varied by patient numeracy and literacy. However, anticipated responses may not correlate with true behavior change. If future research justifies the clinical use of genetic testing to motivate behavior change, it may be important to assess how patient characteristics modify that motivational effect.

Modifications to the Patient Rule-Induction Method that utilize non-additive combinations of genetic and environmental effects to define partitions that predict ischemic heart disease

PubMed Central

Dyson, Greg; Frikke-Schmidt, Ruth; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Sing, Charles F.

2009-01-01

This paper extends the Patient Rule-Induction Method (PRIM) for modeling cumulative incidence of disease developed by Dyson et al. (2007) to include the simultaneous consideration of non-additive combinations of predictor variables, a significance test of each combination, an adjustment for multiple testing and a confidence interval for the estimate of the cumulative incidence of disease in each partition. We employ the partitioning algorithm component of the Combinatorial Partitioning Method (CPM) to construct combinations of predictors, permutation testing to assess the significance of each combination, theoretical arguments for incorporating a multiple testing adjustment and bootstrap resampling to produce the confidence intervals. An illustration of this revised PRIM utilizing a sample of 2258 European male participants from the Copenhagen City Heart Study is presented that assesses the utility of genetic variants in predicting the presence of ischemic heart disease beyond the established risk factors. PMID:19025787

Implementing genomic medicine in pathology.

PubMed

Williams, Eli S; Hegde, Madhuri

2013-07-01

The finished sequence of the Human Genome Project, published 50 years after Watson and Crick's seminal paper on the structure of DNA, pushed human genetics into the public eye and ushered in the genomic era. A significant, if overlooked, aspect of the race to complete the genome was the technology that propelled scientists to the finish line. DNA sequencing technologies have become more standardized, automated, and capable of higher throughput. This technology has continued to grow at an astounding rate in the decade since the Human Genome Project was completed. Today, massively parallel sequencing, or next-generation sequencing (NGS), allows the detection of genetic variants across the entire genome. This ability has led to the identification of new causes of disease and is changing the way we categorize, treat, and manage disease. NGS approaches such as whole-exome sequencing and whole-genome sequencing are rapidly becoming an affordable genetic testing strategy for the clinical laboratory. One test can now provide vast amounts of health information pertaining not only to the disease of interest, but information that may also predict adult-onset disease, reveal carrier status for a rare disease and predict drug responsiveness. The issue of what to do with these incidental findings, along with questions pertaining to NGS testing strategies, data interpretation and storage, and applying genetic testing results into patient care, remains without a clear answer. This review will explore these issues and others relevant to the implementation of NGS in the clinical laboratory.

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands.

PubMed

Weinreich, Stephanie S; Bosma, Astrid; Henneman, Lidewij; Rigter, Tessel; Spruijt, Carla M J; Grimbergen, Anneliese J E M A; Breuning, Martijn H; de Koning, Eelco J P; Losekoot, Monique; Cornel, Martina C

2015-01-01

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

Integrated genetic and epigenetic prediction of coronary heart disease in the Framingham Heart Study.

PubMed

Dogan, Meeshanthini V; Grumbach, Isabella M; Michaelson, Jacob J; Philibert, Robert A

2018-01-01

An improved method for detecting coronary heart disease (CHD) could have substantial clinical impact. Building on the idea that systemic effects of CHD risk factors are a conglomeration of genetic and environmental factors, we use machine learning techniques and integrate genetic, epigenetic and phenotype data from the Framingham Heart Study to build and test a Random Forest classification model for symptomatic CHD. Our classifier was trained on n = 1,545 individuals and consisted of four DNA methylation sites, two SNPs, age and gender. The methylation sites and SNPs were selected during the training phase. The final trained model was then tested on n = 142 individuals. The test data comprised of individuals removed based on relatedness to those in the training dataset. This integrated classifier was capable of classifying symptomatic CHD status of those in the test set with an accuracy, sensitivity and specificity of 78%, 0.75 and 0.80, respectively. In contrast, a model using only conventional CHD risk factors as predictors had an accuracy and sensitivity of only 65% and 0.42, respectively, but with a specificity of 0.89 in the test set. Regression analyses of the methylation signatures illustrate our ability to map these signatures to known risk factors in CHD pathogenesis. These results demonstrate the capability of an integrated approach to effectively model symptomatic CHD status. These results also suggest that future studies of biomaterial collected from longitudinally informative cohorts that are specifically characterized for cardiac disease at follow-up could lead to the introduction of sensitive, readily employable integrated genetic-epigenetic algorithms for predicting onset of future symptomatic CHD.

Behavioural mediators of genetic life-history trade-offs: a test of the pace-of-life syndrome hypothesis in field crickets.

PubMed

Santostefano, Francesca; Wilson, Alastair J; Niemelä, Petri T; Dingemanse, Niels J

2017-10-11

The pace-of-life syndrome (POLS) hypothesis predicts associations between life history and 'risky' behaviours. Individuals with 'fast' lifestyles should develop faster, reproduce earlier, exhibit more risk-prone behaviours, and die sooner than those with 'slow' lifestyles. While support for POLS has been equivocal to date, studies have relied on individual-level (phenotypic) patterns in which genetic trade-offs may be masked by environmental effects on phenotypes. We estimated genetic correlations between life history (development, lifespan, size) and risky behaviours (exploration, aggression) in a pedigreed population of Mediterranean field crickets ( Gryllus bimaculatus ). Path analyses showed that behaviours mediated some genetic relationships between life history traits, though not those involved in trade-offs. Thus, while specific predictions of POLS theory were not supported, genetic integration of behaviour and life history was present. This implies a major role for risky behaviours in life history evolution. © 2017 The Author(s).

Population Diversity and Dispersal of Two Species of Stoneflies (Order Plecoptera) Within Four Watersheds of Northeastern Ohio.

NASA Astrophysics Data System (ADS)

Yasick, A. L.; Wolin, J. A.; Krebs, R. A.

2005-05-01

This study investigates two species of stoneflies with potentially opposing dispersal capabilities and genetic structure within four watersheds in the Lake Erie drainage system of Northeast Ohio. This research is two fold; it provides information on genetic variation of two understudied aquatic invertebrate species and the impact of human land-use practices on this variation. Populations of Allocapnia recta, a winter emerging stonefly are predicted to have the least genetic variation within the four watersheds and most differences among sites due to its rudimentary wing structure and winter emergence. Leuctra tenuis is predicted to have greater genetic variability within sites and fewer differences among sites because of its higher migration potential. In both species, models of isolation by distance will be tested. Distinct polymorphisms exist within the 16s rRNA region of A. recta suggesting that this fragment has sufficient variation to address these questions.

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

PubMed

Syngal, Sapna; Brand, Randall E; Church, James M; Giardiello, Francis M; Hampel, Heather L; Burt, Randall W

2015-02-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

PubMed Central

Syngal, Sapna; Brand, Randall E.; Church, James M.; Giardiello, Francis M.; Hampel, Heather L.; Burt, Randall W.

2015-01-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. PMID:25645574

A Community Challenge for Inferring Genetic Predictors of Gene Essentialities through Analysis of a Functional Screen of Cancer Cell Lines* | Office of Cancer Genomics

Cancer.gov

We report the results of a DREAM challenge designed to predict relative genetic essentialities based on a novel dataset testing 98,000 shRNAs against 149 molecularly characterized cancer cell lines. We analyzed the results of over 3,000 submissions over a period of 4 months.

A Community Challenge for Inferring Genetic Predictors of Gene Essentialities through Analysis of a Functional Screen of Cancer Cell Lines. | Office of Cancer Genomics

Cancer.gov

We report the results of a DREAM challenge designed to predict relative genetic essentialities based on a novel dataset testing 98,000 shRNAs against 149 molecularly characterized cancer cell lines. We analyzed the results of over 3,000 submissions over a period of 4 months.

4th Annual Pharmacogenomics and Medicine Lectures.

PubMed

Oestreicher, P

2001-08-01

In the future, pharmacogenomics will play an important role in the treatment of patients by making it possible to predict drug response based on an individual's genetic make-up. Similarly, pharmacogenomics may be used to reduce the probability that adverse effects will occur. The use of a patient's genetic information will lead to greater predictability in clinical outcomes and personalisation of medical care. Pharmacogenomic information can also aid in drug development by helping to select individuals that are likely to respond to a medication for participation in clinical trials. Integration of pharmacogenomics into the healthcare system has a number of potential economic benefits, including reduced costs of healthcare and drug discovery. The FDA has no specific plans to regulate therapy-guiding pharmacogenomic tests, which are different from diagnostic genetic tests. There are a number of ethical issues related to pharmacogenomics, including the credibility of the system for protecting the rights and welfare of human research subjects, general concerns about genetic research, privacy issues and equitable distribution of the technology. To ensure integration of pharmacogenomics into the healthcare system it will be important to obtain public support through education about the benefits and risks of this technology.

How SNP chips will advance our knowledge of factors controlling puberty and aid in selecting replacement females

USDA-ARS?s Scientific Manuscript database

The promise of genomic selection is that genetic potential can be accurately predicted from genotypes. Simple deoxyribonucleic acid (DNA) tests might replace low accuracy predictions based on performance and pedigree for expensive or lowly heritable measures of puberty and fertility. The promise i...

How single nucleotide polymorphism chips will advance our knowledge of factors controlling puberty and aid in selecting replacement beef females

USDA-ARS?s Scientific Manuscript database

The promise of genomic selection is accurate prediction of animals' genetic potential from their genotypes. Simple DNA tests might replace low accuracy predictions for expensive or lowly heritable measures of puberty and fertility based on performance and pedigree. Knowing which DNA variants affec...

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement.

PubMed

Webborn, Nick; Williams, Alun; McNamee, Mike; Bouchard, Claude; Pitsiladis, Yannis; Ahmetov, Ildus; Ashley, Euan; Byrne, Nuala; Camporesi, Silvia; Collins, Malcolm; Dijkstra, Paul; Eynon, Nir; Fuku, Noriyuki; Garton, Fleur C; Hoppe, Nils; Holm, Søren; Kaye, Jane; Klissouras, Vassilis; Lucia, Alejandro; Maase, Kamiel; Moran, Colin; North, Kathryn N; Pigozzi, Fabio; Wang, Guan

2015-12-01

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Identifying future models for delivering genetic services: a nominal group study in primary care

PubMed Central

Elwyn, Glyn; Edwards, Adrian; Iredale, Rachel; Davies, Peter; Gray, Jonathon

2005-01-01

Background To enable primary care medical practitioners to generate a range of possible service delivery models for genetic counselling services and critically assess their suitability. Methods Modified nominal group technique using in primary care professional development workshops. Results 37 general practitioners in Wales, United Kingdom too part in the nominal group process. The practitioners who attended did not believe current systems were sufficient to meet anticipated demand for genetic services. A wide range of different service models was proposed, although no single option emerged as a clear preference. No argument was put forward for genetic assessment and counselling being central to family practice, neither was there a voice for the view that the family doctor should become skilled at advising patients about predictive genetic testing and be able to counsel patients about the wider implications of genetic testing for patients and their family members, even for areas such as common cancers. Nevertheless, all the preferred models put a high priority on providing the service in the community, and often co-located in primary care, by clinicians who had developed expertise. Conclusion There is a need for a wider debate about how healthcare systems address individual concerns about genetic concerns and risk, especially given the increasing commercial marketing of genetic tests. PMID:15831099

Predictive genetic testing for the identification of high-risk groups: a simulation study on the impact of predictive ability

PubMed Central

2011-01-01

Background Genetic risk models could potentially be useful in identifying high-risk groups for the prevention of complex diseases. We investigated the performance of this risk stratification strategy by examining epidemiological parameters that impact the predictive ability of risk models. Methods We assessed sensitivity, specificity, and positive and negative predictive value for all possible risk thresholds that can define high-risk groups and investigated how these measures depend on the frequency of disease in the population, the frequency of the high-risk group, and the discriminative accuracy of the risk model, as assessed by the area under the receiver-operating characteristic curve (AUC). In a simulation study, we modeled genetic risk scores of 50 genes with equal odds ratios and genotype frequencies, and varied the odds ratios and the disease frequency across scenarios. We also performed a simulation of age-related macular degeneration risk prediction based on published odds ratios and frequencies for six genetic risk variants. Results We show that when the frequency of the high-risk group was lower than the disease frequency, positive predictive value increased with the AUC but sensitivity remained low. When the frequency of the high-risk group was higher than the disease frequency, sensitivity was high but positive predictive value remained low. When both frequencies were equal, both positive predictive value and sensitivity increased with increasing AUC, but higher AUC was needed to maximize both measures. Conclusions The performance of risk stratification is strongly determined by the frequency of the high-risk group relative to the frequency of disease in the population. The identification of high-risk groups with appreciable combinations of sensitivity and positive predictive value requires higher AUC. PMID:21797996

The ties that bind: genetic relatedness predicts the fission and fusion of social groups in wild African elephants.

PubMed

Archie, Elizabeth A; Moss, Cynthia J; Alberts, Susan C

2006-03-07

Many social animals live in stable groups. In contrast, African savannah elephants (Loxodonta africana) live in unusually fluid, fission-fusion societies. That is, 'core' social groups are composed of predictable sets of individuals; however, over the course of hours or days, these groups may temporarily divide and reunite, or they may fuse with other social groups to form much larger social units. Here, we test the hypothesis that genetic relatedness predicts patterns of group fission and fusion among wild, female African elephants. Our study of a single Kenyan population spans 236 individuals in 45 core social groups, genotyped at 11 microsatellite and one mitochondrial DNA (mtDNA) locus. We found that genetic relatedness predicted group fission; adult females remained with their first order maternal relatives when core groups fissioned temporarily. Relatedness also predicted temporary fusion between social groups; core groups were more likely to fuse with each other when the oldest females in each group were genetic relatives. Groups that shared mtDNA haplotypes were also significantly more likely to fuse than groups that did not share mtDNA. Our results suggest that associations between core social groups persist for decades after the original maternal kin have died. We discuss these results in the context of kin selection and its possible role in the evolution of elephant sociality.

The genetics of phaeochromocytoma: using clinical features to guide genetic testing.

PubMed

Jafri, Mariam; Maher, Eamonn R

2012-02-01

Phaeochromocytoma is a rare, usually benign, tumour predominantly managed by endocrinologists. Over the last decade, major advances have been made in understanding the molecular genetic basis of adrenal and extra-adrenal phaeochromocytoma (also referred to as adrenal phaeochromocytoma (aPCA) and extra-adrenal functional paraganglioma (eFPGL)). In contrast to the previously held belief that only 10% of cases had a genetic component, currently about one-third of all aPCA/eFPGL cases are thought to be attributable to germline mutations in at least nine genes (NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, MAX and VHL). Recognition of inherited cases of aPCA/eFPGL is critical for optimal patient management. Thus, the identification of a germline mutation can predict risks of malignancy, recurrent disease, associated non-chromaffin tumours and risks to other family members. Mutation carriers should be offered specific surveillance programmes (according to the relevant gene). In this review, we will describe the genetics of aPCA/eFPGL and strategies for genetic testing.

Soil properties drive a negative correlation between species diversity and genetic diversity in a tropical seasonal rainforest

PubMed Central

Xu, Wumei; Liu, Lu; He, Tianhua; Cao, Min; Sha, Liqing; Hu, Yuehua; Li, Qiaoming; Li, Jie

2016-01-01

A negative species-genetic diversity correlation (SGDC) could be predicted by the niche variation hypothesis, whereby an increase in species diversity within community reduces the genetic diversity of the co-occurring species because of the reduction in average niche breadth; alternatively, competition could reduce effective population size and therefore genetic diversity of the species within community. We tested these predictions within a 20 ha tropical forest dynamics plot (FDP) in the Xishuangbanna tropical seasonal rainforest. We established 15 plots within the FDP and investigated the soil properties, tree diversity, and genetic diversity of a common tree species Beilschmiedia roxburghiana within each plot. We observed a significant negative correlation between tree diversity and the genetic diversity of B. roxburghiana within the communities. Using structural equation modeling, we further determined that the inter-plot environmental characteristics (soil pH and phosphorus availability) directly affected tree diversity and that the tree diversity within the community determined the genetic diversity of B. roxburghiana. Increased soil pH and phosphorus availability might promote the coexistence of more tree species within community and reduce genetic diversity of B. roxburghiana for the reduced average niche breadth; alternatively, competition could reduce effective population size and therefore genetic diversity of B. roxburghiana within community. PMID:26860815

Soil properties drive a negative correlation between species diversity and genetic diversity in a tropical seasonal rainforest.

PubMed

Xu, Wumei; Liu, Lu; He, Tianhua; Cao, Min; Sha, Liqing; Hu, Yuehua; Li, Qiaoming; Li, Jie

2016-02-10

A negative species-genetic diversity correlation (SGDC) could be predicted by the niche variation hypothesis, whereby an increase in species diversity within community reduces the genetic diversity of the co-occurring species because of the reduction in average niche breadth; alternatively, competition could reduce effective population size and therefore genetic diversity of the species within community. We tested these predictions within a 20 ha tropical forest dynamics plot (FDP) in the Xishuangbanna tropical seasonal rainforest. We established 15 plots within the FDP and investigated the soil properties, tree diversity, and genetic diversity of a common tree species Beilschmiedia roxburghiana within each plot. We observed a significant negative correlation between tree diversity and the genetic diversity of B. roxburghiana within the communities. Using structural equation modeling, we further determined that the inter-plot environmental characteristics (soil pH and phosphorus availability) directly affected tree diversity and that the tree diversity within the community determined the genetic diversity of B. roxburghiana. Increased soil pH and phosphorus availability might promote the coexistence of more tree species within community and reduce genetic diversity of B. roxburghiana for the reduced average niche breadth; alternatively, competition could reduce effective population size and therefore genetic diversity of B. roxburghiana within community.

Attitudes and anticipated reactions to genetic testing for cancer among patients in Mexico City.

PubMed

Romero-Hidalgo, Sandra; Urraca, Nora; Parra, Dionisio; Villa, Antonio R; Lisker, Rubén; Carnevale, Alessandra

2009-08-01

The aim of this study was to investigate the attitudes toward cancer predictive genetic testing in a group of non-high-risk women and men and to analyze the factors that may influence their intention to use these tests. We studied a sample of 859 outpatient women and men attending the four tertiary care hospitals of the ISSSTE (Institute of Social Security and Services for Government Employees) in Mexico City. Subjects between the ages of 30 and 74 years with no present or past history of cancer were asked to answer a questionnaire through face-to-face interview. Two different questionnaires were designed, one for women and the other for men, regarding genetic testing of a high-risk gene for breast and prostate cancer, respectively. Descriptive statistics and univariate comparisons were carried out using chi-square test, Wilcoxon's signed rank test, and Friedman test. Multivariate analysis was performed using logistic regression technique. Results showed that the majority of women attended clinics for regular check-ups and for performing screening tests to detect breast cancer, and men did not follow this pattern regarding prostate cancer. Women were more motivated to get genetic testing, more aware about its benefits, and more concerned about having cancer than men.

The prospect of predictive testing for personal risk: attitudes and decision making.

PubMed

Wroe, A L; Salkovskis, P M; Rimes, K A

1998-06-01

As predictive tests for medical problems such as genetic disorders become more widely available, it becomes increasingly important to understand the processes involved in the decision whether or not to seek testing. This study investigates the decision to pursue the possibility of testing. Individuals (one group who had already contemplated the possibility of predictive testing and one group who had not) were asked to consider predictive testing for several diseases. They rated the likelihood of opting for testing and specified the reasons which they believed had affected their decision. The ratio of the numbers of reasons stated for testing and the numbers of reasons stated against testing was a good predictor of the stated likelihood of testing, particularly when the reasons were weighted by utility (importance). Those who had previously contemplated testing specified more emotional reasons. It is proposed that the decision process is internally logical although it may seem illogical to others due to there being idiosyncratic premises (or reasons) upon which the decision is based. It is concluded that the Utility Theory is a useful basis for describing how people make decisions related to predictive testing; modifications of the theory are proposed.

Computational allergenicity prediction of transgenic proteins expressed in genetically modified crops.

PubMed

Verma, Alok Kumar; Misra, Amita; Subash, Swarna; Das, Mukul; Dwivedi, Premendra D

2011-09-01

Development of genetically modified (GM) crops is on increase to improve food quality, increase harvest yields, and reduce the dependency on chemical pesticides. Before their release in marketplace, they should be scrutinized for their safety. Several guidelines of different regulatory agencies like ILSI, WHO Codex, OECD, and so on for allergenicity evaluation of transgenics are available and sequence homology analysis is the first test to determine the allergenic potential of inserted proteins. Therefore, to test and validate, 312 allergenic, 100 non-allergenic, and 48 inserted proteins were assessed for sequence similarity using 8-mer, 80-mer, and full FASTA search. On performing sequence homology studies, ~94% the allergenic proteins gave exact matches for 8-mer and 80-mer homology. However, 20 allergenic proteins showed non-allergenic behavior. Out of 100 non-allergenic proteins, seven qualified as allergens. None of the inserted proteins demonstrated allergenic behavior. In order to improve the predictability, proteins showing anomalous behavior were tested by Algpred and ADFS separately. Use of Algpred and ADFS softwares reduced the tendency of false prediction to a great extent (74-78%). In conclusion, routine sequence homology needs to be coupled with some other bioinformatic method like ADFS/Algpred to reduce false allergenicity prediction of novel proteins.

Genetic risk prediction and neurobiological understanding of alcoholism.

PubMed

Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; Kiefer, F; Kiefe, F; Wodarz, N; Müller-Myhsok, B; Dahmen, N; Nöthen, M; Sherva, R; Farrer, L; Smith, A H; Kranzler, H R; Rietschel, M; Gelernter, J; Niculescu, A B

2014-05-20

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.

Ecology has contrasting effects on genetic variation within species versus rates of molecular evolution across species in water beetles.

PubMed

Fujisawa, Tomochika; Vogler, Alfried P; Barraclough, Timothy G

2015-01-22

Comparative analysis is a potentially powerful approach to study the effects of ecological traits on genetic variation and rate of evolution across species. However, the lack of suitable datasets means that comparative studies of correlates of genetic traits across an entire clade have been rare. Here, we use a large DNA-barcode dataset (5062 sequences) of water beetles to test the effects of species ecology and geographical distribution on genetic variation within species and rates of molecular evolution across species. We investigated species traits predicted to influence their genetic characteristics, such as surrogate measures of species population size, latitudinal distribution and habitat types, taking phylogeny into account. Genetic variation of cytochrome oxidase I in water beetles was positively correlated with occupancy (numbers of sites of species presence) and negatively with latitude, whereas substitution rates across species depended mainly on habitat types, and running water specialists had the highest rate. These results are consistent with theoretical predictions from nearly-neutral theories of evolution, and suggest that the comparative analysis using large databases can give insights into correlates of genetic variation and molecular evolution.

Evolving hard problems: Generating human genetics datasets with a complex etiology.

PubMed

Himmelstein, Daniel S; Greene, Casey S; Moore, Jason H

2011-07-07

A goal of human genetics is to discover genetic factors that influence individuals' susceptibility to common diseases. Most common diseases are thought to result from the joint failure of two or more interacting components instead of single component failures. This greatly complicates both the task of selecting informative genetic variants and the task of modeling interactions between them. We and others have previously developed algorithms to detect and model the relationships between these genetic factors and disease. Previously these methods have been evaluated with datasets simulated according to pre-defined genetic models. Here we develop and evaluate a model free evolution strategy to generate datasets which display a complex relationship between individual genotype and disease susceptibility. We show that this model free approach is capable of generating a diverse array of datasets with distinct gene-disease relationships for an arbitrary interaction order and sample size. We specifically generate eight-hundred Pareto fronts; one for each independent run of our algorithm. In each run the predictiveness of single genetic variation and pairs of genetic variants have been minimized, while the predictiveness of third, fourth, or fifth-order combinations is maximized. Two hundred runs of the algorithm are further dedicated to creating datasets with predictive four or five order interactions and minimized lower-level effects. This method and the resulting datasets will allow the capabilities of novel methods to be tested without pre-specified genetic models. This allows researchers to evaluate which methods will succeed on human genetics problems where the model is not known in advance. We further make freely available to the community the entire Pareto-optimal front of datasets from each run so that novel methods may be rigorously evaluated. These 76,600 datasets are available from http://discovery.dartmouth.edu/model_free_data/.

Prediction accuracies for growth and wood attributes of interior spruce in space using genotyping-by-sequencing.

PubMed

Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Chen, Charles; Porth, Ilga; El-Kassaby, Yousry A

2015-05-09

Genomic selection (GS) in forestry can substantially reduce the length of breeding cycle and increase gain per unit time through early selection and greater selection intensity, particularly for traits of low heritability and late expression. Affordable next-generation sequencing technologies made it possible to genotype large numbers of trees at a reasonable cost. Genotyping-by-sequencing was used to genotype 1,126 Interior spruce trees representing 25 open-pollinated families planted over three sites in British Columbia, Canada. Four imputation algorithms were compared (mean value (MI), singular value decomposition (SVD), expectation maximization (EM), and a newly derived, family-based k-nearest neighbor (kNN-Fam)). Trees were phenotyped for several yield and wood attributes. Single- and multi-site GS prediction models were developed using the Ridge Regression Best Linear Unbiased Predictor (RR-BLUP) and the Generalized Ridge Regression (GRR) to test different assumption about trait architecture. Finally, using PCA, multi-trait GS prediction models were developed. The EM and kNN-Fam imputation methods were superior for 30 and 60% missing data, respectively. The RR-BLUP GS prediction model produced better accuracies than the GRR indicating that the genetic architecture for these traits is complex. GS prediction accuracies for multi-site were high and better than those of single-sites while multi-site predictability produced the lowest accuracies reflecting type-b genetic correlations and deemed unreliable. The incorporation of genomic information in quantitative genetics analyses produced more realistic heritability estimates as half-sib pedigree tended to inflate the additive genetic variance and subsequently both heritability and gain estimates. Principle component scores as representatives of multi-trait GS prediction models produced surprising results where negatively correlated traits could be concurrently selected for using PCA2 and PCA3. The application of GS to open-pollinated family testing, the simplest form of tree improvement evaluation methods, was proven to be effective. Prediction accuracies obtained for all traits greatly support the integration of GS in tree breeding. While the within-site GS prediction accuracies were high, the results clearly indicate that single-site GS models ability to predict other sites are unreliable supporting the utilization of multi-site approach. Principle component scores provided an opportunity for the concurrent selection of traits with different phenotypic optima.

Understanding of multigene test results among males undergoing germline testing for inherited prostate cancer: Implications for genetic counseling.

PubMed

Giri, Veda N; Obeid, Elias; Hegarty, Sarah E; Gross, Laura; Bealin, Lisa; Hyatt, Colette; Fang, Carolyn Y; Leader, Amy

2018-04-14

Genetic testing (GT) for prostate cancer (PCA) is rising, with limited insights regarding genetic counseling (GC) needs of males. Genetic Evaluation of Men (GEM) is a prospective multigene testing study for inherited PCA. Men undergoing GC were surveyed on knowledge of cancer risk and genetics (CRG) and understanding of personal GT results to identify GC needs. GEM participants with or high-risk for PCA were recruited. Pre-test GC was in-person, with video and handout, or via telehealth. Post-test disclosure was in-person, by phone, or via telehealth. Clinical and family history data were obtained from participant surveys and medical records. Participants completed measures of knowledge of CRG, literacy, and numeracy pre-test and post-test. Understanding of personal genetic results was assessed post-test. Factors associated with knowledge of CRG and understanding of personal genetic results were examined using multivariable linear regression or McNemar's test. Among 109 men who completed pre- and post-GT surveys, multivariable analysis revealed family history meeting hereditary cancer syndrome (HCS) criteria was significantly predictive of higher baseline knowledge (P = 0.040). Of 101 men who responded definitively regarding understanding of results, 13 incorrectly reported their result (McNemar's P < 0.001). Factors significantly associated with discordance between reported and actual results included having a variant of uncertain significance (VUS) (P < 0.001) and undergoing GC via pre-test video and post-test phone disclosure (P = 0.015). While meeting criteria for HCS was associated with higher knowledge of CRG, understanding of personal GT results was lacking among a subset of males with VUS. A more exploratory finding was lack of understanding of results among men who underwent GC utilizing video and phone. Studies optimizing GC strategies for males undergoing multigene testing for inherited PCA are warranted. © 2018 Wiley Periodicals, Inc.

What Are the Chances My Child Will Inherit a Condition?

MedlinePlus

... Predictive testing Pregnancy related screening Reimbursement for Genetic ... behavior. There are steps you can take to prevent disease, lower your risk, and find problems early when most treatments work ...

PHENOTYPIC AND GENETIC HETEROGENEITY AMONG SUBJECTS WITH MILD AIRFLOW OBSTRUCTION IN COPDGENE

PubMed Central

Lee, Jin Hwa; Cho, Michael H.; McDonald, Merry-Lynn N.; Hersh, Craig P.; Castaldi, Peter J.; Crapo, James D.; Wan, Emily S.; Dy, Jennifer G.; Chang, Yale; Regan, Elizabeth A.; Hardin, Megan; DeMeo, Dawn L.; Silverman, Edwin K.

2014-01-01

Background Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1). Methods Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD1 and smoking control subjects. Results K-means clustering of GOLD 1 subjects identified putative “near-normal”, “airway-predominant”, “emphysema-predominant” and “lowest FEV1 % predicted” subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1 % predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects. Conclusions Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity. PMID:25154699

Looking at genes in the workplace.

PubMed

Holden, C

1982-07-23

The Office of Technology Assessment recently testified at a congressional hearing that many corporations are considering genetic screening of employees. Biochemical genetic screening of "susceptible" workers is aimed at identifying individuals unsuitable for specific jobs, and cytogenic monitoring involves the testing of groups of workers for chromosome aberrations that might occur as a result of exposure to chemicals. The apparent surge of interest in such testing requires that several legal, ethical, and policy issues be addressed, including the potential for discrimination, the misuse of screening as an alternative to cleaning up the workplace, the predictive capability of the tests, and the necessity for the development of guidelines for screening programs.

Crying without a cause and being easily upset in two-year-olds: heritability and predictive power of behavioral problems.

PubMed

Groen-Blokhuis, Maria M; Middeldorp, Christel M; M van Beijsterveldt, Catharina E; Boomsma, Dorret I

2011-10-01

In order to estimate the influence of genetic and environmental factors on 'crying without a cause' and 'being easily upset' in 2-year-old children, a large twin study was carried out. Prospective data were available for ~18,000 2-year-old twin pairs from the Netherlands Twin Register. A bivariate genetic analysis was performed using structural equation modeling in the Mx software package. The influence of maternal personality characteristics and demographic and lifestyle factors was tested to identify specific risk factors that may underlie the shared environment of twins. Furthermore, it was tested whether crying without a cause and being easily upset were predictive of later internalizing, externalizing and attention problems. Crying without a cause yielded a heritability estimate of 60% in boys and girls. For easily upset, the heritability was estimated at 43% in boys and 31% in girls. The variance explained by shared environment varied between 35% and 63%. The correlation between crying without a cause and easily upset (r = .36) was explained both by genetic and shared environmental factors. Birth cohort, gestational age, socioeconomic status, parental age, parental smoking behavior and alcohol use during pregnancy did not explain the shared environmental component. Neuroticism of the mother explained a small proportion of the additive genetic, but not of the shared environmental effects for easily upset. Crying without a cause and being easily upset at age 2 were predictive of internalizing, externalizing and attention problems at age 7, with effect sizes of .28-.42. A large influence of shared environmental factors on crying without a cause and easily upset was detected. Although these effects could be specific to these items, we could not explain them by personality characteristics of the mother or by demographic and lifestyle factors, and we recognize that these effects may reflect other maternal characteristics. A substantial influence of genetic factors was found for the two items, which are predictive of later behavioral problems.

Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis

PubMed Central

King, Caitriona; Barton, David E

2006-01-01

Background Hereditary haemochromatosis (HH) is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y) of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D). Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing. Methods A survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment. Results Consensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines. Conclusion An agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing. PMID:17134494

Awareness, attitudes and perspectives of direct-to-consumer genetic testing in Greece: a survey of potential consumers.

PubMed

Mavroidopoulou, Vasiliki; Xera, Ellie; Mollaki, Vasiliki

2015-09-01

Direct-to-consumer genetic testing (DTCGT) is now offered by numerous companies. The present survey aimed to explore awareness, interest, reasons to take and refuse DTCGT, and understanding of results amongst 725 higher education students in Greece. A third of the responders were aware of DTCGT and interest was dependent on cost. More than 60% of the participants would undergo DTCGT to learn more about their health, to warn their children, so that their doctor can monitor their health and change their lifestyle. Nevertheless, they would prefer to consult their doctor first and expressed concerned about their personal data. After receiving results from a hypothetical DTC genetic test predicting higher risk for colon cancer, 59.5% of the responders thought that they could understand the results but 46.1% believed that the results have diagnostic value. In total, 83.6% of the participants would ask their doctor to explain the results and 70.4% would discuss results with their family. In conclusion, the majority of higher education students in Greece appreciate the benefits of genetic testing but with the involvement of their doctor. A physician's participation in the process and informing the public about the true value of genetic testing, are crucial to avoid misinterpretation of DTCGT results.

The clinical introduction of genetic testing for Alzheimer disease. An ethical perspective.

PubMed

Post, S G; Whitehouse, P J; Binstock, R H; Bird, T D; Eckert, S K; Farrer, L A; Fleck, L M; Gaines, A D; Juengst, E T; Karlinsky, H; Miles, S; Murray, T H; Quaid, K A; Relkin, N R; Roses, A D; St George-Hyslop, P H; Sachs, G A; Steinbock, B; Truschke, E F; Zinn, A B

1997-03-12

Primary caregivers should be aware of recent progress in the genetics of Alzheimer disease (AD) and of the clinical and ethical considerations raised regarding the introduction of genetic testing for purposes of disease prediction and susceptibility (risk) analysis in asymptomatic individuals and diagnosis in patients who present clinically with dementia. This statement addresses arguments for and against clinical genetic testing. The 20 participants were selected by the investigators (S.G.P., T.H.M., A.B.Z., and P.J.W.) to achieve balance in the areas of genetics, counseling, ethics, and public policy, and to include leadership from related consensus projects. The consensus group met twice in closed meetings and carried on extensive correspondence over 2 years (1995-1997). The project was supported by the National Human Genome Research Institute of the National Institutes of Health. All 4 involved chromosomes were discussed in group meetings against a background of information from several focus group sessions with AD-affected families. The focus groups comprised volunteers identified by the Cleveland Area Chapter of the Alzheimer's Disease and Related Disorders Association and represented a variety of ethnic populations. The first draft was written in April 1996 by the principal investigator (S.G.P.) after the consensus group had met twice. The draft was mailed to all consensus group members 3 times over 6 months for extensive response and redrafting by the principal investigator until all members were satisfied. Except for autosomal dominant early-onset families, genetic testing in asymptomatic individuals is unwarranted. Use of APOE genetic testing as a diagnostic adjunct in patients already presenting with dementia may prove useful but it remains under investigation. The premature introduction of genetic testing and possible adverse consequences are to be avoided.

Predicting Silk Fiber Mechanical Properties through Multiscale Simulation and Protein Design.

PubMed

Rim, Nae-Gyune; Roberts, Erin G; Ebrahimi, Davoud; Dinjaski, Nina; Jacobsen, Matthew M; Martín-Moldes, Zaira; Buehler, Markus J; Kaplan, David L; Wong, Joyce Y

2017-08-14

Silk is a promising material for biomedical applications, and much research is focused on how application-specific, mechanical properties of silk can be designed synthetically through proper amino acid sequences and processing parameters. This protocol describes an iterative process between research disciplines that combines simulation, genetic synthesis, and fiber analysis to better design silk fibers with specific mechanical properties. Computational methods are used to assess the protein polymer structure as it forms an interconnected fiber network through shearing and how this process affects fiber mechanical properties. Model outcomes are validated experimentally with the genetic design of protein polymers that match the simulation structures, fiber fabrication from these polymers, and mechanical testing of these fibers. Through iterative feedback between computation, genetic synthesis, and fiber mechanical testing, this protocol will enable a priori prediction capability of recombinant material mechanical properties via insights from the resulting molecular architecture of the fiber network based entirely on the initial protein monomer composition. This style of protocol may be applied to other fields where a research team seeks to design a biomaterial with biomedical application-specific properties. This protocol highlights when and how the three research groups (simulation, synthesis, and engineering) should be interacting to arrive at the most effective method for predictive design of their material.

Does perceived risk predict breast cancer screening use? Findings from a prospective cohort study of female relatives from the Ontario site of the breast cancer family registry.

PubMed

Walker, Meghan J; Mirea, Lucia; Glendon, Gord; Ritvo, Paul; Andrulis, Irene L; Knight, Julia A; Chiarelli, Anna M

2014-08-01

While the relationship between perceived risk and breast cancer screening use has been studied extensively, most studies are cross-sectional. We prospectively examined this relationship among 913 women, aged 25-72 with varying levels of familial breast cancer risk from the Ontario site of the Breast Cancer Family Registry. Associations between perceived lifetime breast cancer risk and subsequent use of mammography, clinical breast examination (CBE) and genetic testing were assessed using logistic regression. Overall, perceived risk did not predict subsequent use of mammography, CBE or genetic testing. Among women at moderate/high familial risk, those reporting a perceived risk greater than 50% were significantly less likely to have a CBE (odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.30-0.91, p = 0.04), and non-significantly less likely to have a mammogram (OR = 0.70, 95% CI: 0.40-1.20, p = 0.70) or genetic test (OR = 0.61, 95% CI: 0.34-1.10, p = 0.09) compared to women reporting a perceived risk of 50%. In contrast, among women at low familial risk, those reporting a perceived risk greater than 50% were non-significantly more likely to have a mammogram (OR = 1.13, 95% CI: 0.59-2.16, p = 0.78), CBE (OR = 1.11, 95% CI: 0.63-1.95, p = 0.74) or genetic test (OR = 1.29, 95% CI: 0.50-3.33, p = 0.35) compared to women reporting a perceived risk of 50%. Perceived risk did not significantly predict screening use overall, however this relationship may be moderated by level of familial risk. Results may inform risk education and management strategies for women with varying levels of familial breast cancer risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

The genetics of hyperuricaemia and gout.

PubMed

Reginato, Anthony M; Mount, David B; Yang, Irene; Choi, Hyon K

2012-10-01

Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular-metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B*5801 alleles could be used to predict these potentially fatal adverse effects.

Plasticity of genetic interactions in metabolic networks of yeast.

PubMed

Harrison, Richard; Papp, Balázs; Pál, Csaba; Oliver, Stephen G; Delneri, Daniela

2007-02-13

Why are most genes dispensable? The impact of gene deletions may depend on the environment (plasticity), the presence of compensatory mechanisms (mutational robustness), or both. Here, we analyze the interaction between these two forces by exploring the condition-dependence of synthetic genetic interactions that define redundant functions and alternative pathways. We performed systems-level flux balance analysis of the yeast (Saccharomyces cerevisiae) metabolic network to identify genetic interactions and then tested the model's predictions with in vivo gene-deletion studies. We found that the majority of synthetic genetic interactions are restricted to certain environmental conditions, partly because of the lack of compensation under some (but not all) nutrient conditions. Moreover, the phylogenetic cooccurrence of synthetically interacting pairs is not significantly different from random expectation. These findings suggest that these gene pairs have at least partially independent functions, and, hence, compensation is only a byproduct of their evolutionary history. Experimental analyses that used multiple gene deletion strains not only confirmed predictions of the model but also showed that investigation of false predictions may both improve functional annotation within the model and also lead to the discovery of higher-order genetic interactions. Our work supports the view that functional redundancy may be more apparent than real, and it offers a unified framework for the evolution of environmental adaptation and mutational robustness.

Family differences in equations for predicting biomass and leaf area in Douglas-fir (Pseudotsuga menziesii var. menziesii).

Treesearch

J.B. St. Clair

1993-01-01

Logarithmic regression equations were developed to predict component biomass and leaf area for an 18-yr-old genetic test of Douglas-fir (Pseudotsuga menziesii [Mirb.] Franco var. menziesii) based on stem diameter or cross-sectional sapwood area. Equations did not differ among open-pollinated families in slope, but intercepts...

Positive perception of pharmacogenetic testing for psychotropic medications

PubMed Central

Lanktree, Matthew B; Zai, Gwyneth; VanderBeek, Laura E; Giuffra, Daniel E; Smithson, David S; Kipp, Lucas B; Dalseg, Timothy R; Speechley, Mark; Kennedy, James L

2014-01-01

Introduction Pharmacogenetics attempts to identify inter-individual genetic differences that are predictive of variable drug response and propensity to side effects, with the prospect of assisting physicians to select the most appropriate drug and dosage for treatment. However, many concerns regarding genetic tests exist. We sought to test the opinions of undergraduate science and medical students in southern Ontario universities toward pharmacogenetic testing. Methods and Results Questionnaires were completed by 910 undergraduate medicine and science students from 2005 to 2007. Despite students' concerns that the results of genetic tests may be used for other purposes without consent (71%) or lead to discrimination (78%), an overwhelming number of students were in favor of pharmacogenetic testing (90%). Discussion To our knowledge, this study is the first to survey a large sample for their attitude toward pharmacogenetic testing for psychotropic medications. Our results indicate that, although concerns remain and scientific advancements are required, respondents were in support of pharmacogenetic testing for medications used to treat schizophrenia. © 2014 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd. PMID:24604560

Impacts of early viability selection on management of inbreeding and genetic diversity in conservation.

PubMed

Grueber, Catherine E; Hogg, Carolyn J; Ivy, Jamie A; Belov, Katherine

2015-04-01

Maintaining genetic diversity is a crucial goal of intensive management of threatened species, particularly for those populations that act as sources for translocation or re-introduction programmes. Most captive genetic management is based on pedigrees and a neutral theory of inheritance, an assumption that may be violated by selective forces operating in captivity. Here, we explore the conservation consequences of early viability selection: differential offspring survival that occurs prior to management or research observations, such as embryo deaths in utero. If early viability selection produces genotypic deviations from Mendelian predictions, it may undermine management strategies intended to minimize inbreeding and maintain genetic diversity. We use empirical examples to demonstrate that straightforward approaches, such as comparing litter sizes of inbred vs. noninbred breeding pairs, can be used to test whether early viability selection likely impacts estimates of inbreeding depression. We also show that comparing multilocus genotype data to pedigree predictions can reveal whether early viability selection drives systematic biases in genetic diversity, patterns that would not be detected using pedigree-based statistics alone. More sophisticated analysis combining genomewide molecular data with pedigree information will enable conservation scientists to test whether early viability selection drives deviations from neutrality across wide stretches of the genome, revealing whether this form of selection biases the pedigree-based statistics and inference upon which intensive management is based. © 2015 John Wiley & Sons Ltd.

Assessment of Genetic and Nongenetic Interactions for the Prediction of Depressive Symptomatology: An Analysis of the Wisconsin Longitudinal Study Using Machine Learning Algorithms

PubMed Central

Roetker, Nicholas S.; Yonker, James A.; Chang, Vicky; Roan, Carol L.; Herd, Pamela; Hauser, Taissa S.; Hauser, Robert M.

2013-01-01

Objectives. We examined depression within a multidimensional framework consisting of genetic, environmental, and sociobehavioral factors and, using machine learning algorithms, explored interactions among these factors that might better explain the etiology of depressive symptoms. Methods. We measured current depressive symptoms using the Center for Epidemiologic Studies Depression Scale (n = 6378 participants in the Wisconsin Longitudinal Study). Genetic factors were 78 single nucleotide polymorphisms (SNPs); environmental factors—13 stressful life events (SLEs), plus a composite proportion of SLEs index; and sociobehavioral factors—18 personality, intelligence, and other health or behavioral measures. We performed traditional SNP associations via logistic regression likelihood ratio testing and explored interactions with support vector machines and Bayesian networks. Results. After correction for multiple testing, we found no significant single genotypic associations with depressive symptoms. Machine learning algorithms showed no evidence of interactions. Naïve Bayes produced the best models in both subsets and included only environmental and sociobehavioral factors. Conclusions. We found no single or interactive associations with genetic factors and depressive symptoms. Various environmental and sociobehavioral factors were more predictive of depressive symptoms, yet their impacts were independent of one another. A genome-wide analysis of genetic alterations using machine learning methodologies will provide a framework for identifying genetic–environmental–sociobehavioral interactions in depressive symptoms. PMID:23927508

Colorectal Cancer Risk Assessment Tool

MedlinePlus

... 11/12/2014 Risk Calculator About the Tool Colorectal Cancer Risk Factors Download SAS and Gauss Code Page ... Rectal Cancer: Prevention, Genetics, Causes Tests to Detect Colorectal Cancer and Polyps Cancer Risk Prediction Resources Update November ...

A comparison of worldwide phonemic and genetic variation in human populations

PubMed Central

Creanza, Nicole; Ruhlen, Merritt; Pemberton, Trevor J.; Rosenberg, Noah A.; Feldman, Marcus W.; Ramachandran, Sohini

2015-01-01

Worldwide patterns of genetic variation are driven by human demographic history. Here, we test whether this demographic history has left similar signatures on phonemes—sound units that distinguish meaning between words in languages—to those it has left on genes. We analyze, jointly and in parallel, phoneme inventories from 2,082 worldwide languages and microsatellite polymorphisms from 246 worldwide populations. On a global scale, both genetic distance and phonemic distance between populations are significantly correlated with geographic distance. Geographically close language pairs share significantly more phonemes than distant language pairs, whether or not the languages are closely related. The regional geographic axes of greatest phonemic differentiation correspond to axes of genetic differentiation, suggesting that there is a relationship between human dispersal and linguistic variation. However, the geographic distribution of phoneme inventory sizes does not follow the predictions of a serial founder effect during human expansion out of Africa. Furthermore, although geographically isolated populations lose genetic diversity via genetic drift, phonemes are not subject to drift in the same way: within a given geographic radius, languages that are relatively isolated exhibit more variance in number of phonemes than languages with many neighbors. This finding suggests that relatively isolated languages are more susceptible to phonemic change than languages with many neighbors. Within a language family, phoneme evolution along genetic, geographic, or cognate-based linguistic trees predicts similar ancestral phoneme states to those predicted from ancient sources. More genetic sampling could further elucidate the relative roles of vertical and horizontal transmission in phoneme evolution. PMID:25605893

Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.

PubMed

Li, Bian; Mendenhall, Jeffrey L; Kroncke, Brett M; Taylor, Keenan C; Huang, Hui; Smith, Derek K; Vanoye, Carlos G; Blume, Jeffrey D; George, Alfred L; Sanders, Charles R; Meiler, Jens

2017-10-01

An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew's correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred. Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools. © 2017 American Heart Association, Inc.

Ethics, genetic testing, and athletic talent: children's best interests, and the right to an open (athletic) future.

PubMed

Camporesi, Silvia; McNamee, Mike J

2016-03-01

In this paper we discuss the ethics of genetics-based talent identification programs in sports. We discuss the validity and reliability of the tests and the claims made by direct to consumer companies, before presenting a range of ethical issues concerning child-parent/guardian relations raised by these tests, which we frame in terms of parental/guardian duties, children's rights, and best interests. We argue that greater ethical emphasis needs to be put on the parental decision on the wellbeing on the child going forward, not on ex post justifications on the basis of good and bad consequences. Best interests decisions made by a third party seem to comprise both subjective and objective elements, but only a holistic approach can do justice to these questions by addressing the wellbeing of the child in a temporal manner and taking into account the child's perspective on its wellbeing. Such decisions must address wider questions of what a good (sports)parent ought do to help the child flourish and how to balance the future-adult focus necessary to nurture talent with the wellbeing of the child in the present. We conclude that current genetic tests for "talent" do not predict aptitude or success to any significant degree and are therefore only marginally pertinent for talent identification. Claims that go beyond current science are culpable and attempt to exploit widespread but naïve perceptions of the efficacy of genetics information to predict athletic futures. Sports physicians and health care professionals involved in sport medicine should therefore discourage the use of these tests. Copyright © 2016 the American Physiological Society.

Random regression models using Legendre orthogonal polynomials to evaluate the milk production of Alpine goats.

PubMed

Silva, F G; Torres, R A; Brito, L F; Euclydes, R F; Melo, A L P; Souza, N O; Ribeiro, J I; Rodrigues, M T

2013-12-11

The objective of this study was to identify the best random regression model using Legendre orthogonal polynomials to evaluate Alpine goats genetically and to estimate the parameters for test day milk yield. On the test day, we analyzed 20,710 records of milk yield of 667 goats from the Goat Sector of the Universidade Federal de Viçosa. The evaluated models had combinations of distinct fitting orders for polynomials (2-5), random genetic (1-7), and permanent environmental (1-7) fixed curves and a number of classes for residual variance (2, 4, 5, and 6). WOMBAT software was used for all genetic analyses. A random regression model using the best Legendre orthogonal polynomial for genetic evaluation of milk yield on the test day of Alpine goats considered a fixed curve of order 4, curve of genetic additive effects of order 2, curve of permanent environmental effects of order 7, and a minimum of 5 classes of residual variance because it was the most economical model among those that were equivalent to the complete model by the likelihood ratio test. Phenotypic variance and heritability were higher at the end of the lactation period, indicating that the length of lactation has more genetic components in relation to the production peak and persistence. It is very important that the evaluation utilizes the best combination of fixed, genetic additive and permanent environmental regressions, and number of classes of heterogeneous residual variance for genetic evaluation using random regression models, thereby enhancing the precision and accuracy of the estimates of parameters and prediction of genetic values.

Evaluation of an ensemble of genetic models for prediction of a quantitative trait.

PubMed

Milton, Jacqueline N; Steinberg, Martin H; Sebastiani, Paola

2014-01-01

Many genetic markers have been shown to be associated with common quantitative traits in genome-wide association studies. Typically these associated genetic markers have small to modest effect sizes and individually they explain only a small amount of the variability of the phenotype. In order to build a genetic prediction model without fitting a multiple linear regression model with possibly hundreds of genetic markers as predictors, researchers often summarize the joint effect of risk alleles into a genetic score that is used as a covariate in the genetic prediction model. However, the prediction accuracy can be highly variable and selecting the optimal number of markers to be included in the genetic score is challenging. In this manuscript we present a strategy to build an ensemble of genetic prediction models from data and we show that the ensemble-based method makes the challenge of choosing the number of genetic markers more amenable. Using simulated data with varying heritability and number of genetic markers, we compare the predictive accuracy and inclusion of true positive and false positive markers of a single genetic prediction model and our proposed ensemble method. The results show that the ensemble of genetic models tends to include a larger number of genetic variants than a single genetic model and it is more likely to include all of the true genetic markers. This increased sensitivity is obtained at the price of a lower specificity that appears to minimally affect the predictive accuracy of the ensemble.

Novel Covariance-Based Neutrality Test of Time-Series Data Reveals Asymmetries in Ecological and Economic Systems

PubMed Central

Burby, Joshua W.; Lacker, Daniel

2016-01-01

Systems as diverse as the interacting species in a community, alleles at a genetic locus, and companies in a market are characterized by competition (over resources, space, capital, etc) and adaptation. Neutral theory, built around the hypothesis that individual performance is independent of group membership, has found utility across the disciplines of ecology, population genetics, and economics, both because of the success of the neutral hypothesis in predicting system properties and because deviations from these predictions provide information about the underlying dynamics. However, most tests of neutrality are weak, based on static system properties such as species-abundance distributions or the number of singletons in a sample. Time-series data provide a window onto a system’s dynamics, and should furnish tests of the neutral hypothesis that are more powerful to detect deviations from neutrality and more informative about to the type of competitive asymmetry that drives the deviation. Here, we present a neutrality test for time-series data. We apply this test to several microbial time-series and financial time-series and find that most of these systems are not neutral. Our test isolates the covariance structure of neutral competition, thus facilitating further exploration of the nature of asymmetry in the covariance structure of competitive systems. Much like neutrality tests from population genetics that use relative abundance distributions have enabled researchers to scan entire genomes for genes under selection, we anticipate our time-series test will be useful for quick significance tests of neutrality across a range of ecological, economic, and sociological systems for which time-series data are available. Future work can use our test to categorize and compare the dynamic fingerprints of particular competitive asymmetries (frequency dependence, volatility smiles, etc) to improve forecasting and management of complex adaptive systems. PMID:27689714

Model-based conservation planning of the genetic diversity of Phellodendron amurense Rupr due to climate change

PubMed Central

Wan, Jizhong; Wang, Chunjing; Yu, Jinghua; Nie, Siming; Han, Shijie; Zu, Yuangang; Chen, Changmei; Yuan, Shusheng; Wang, Qinggui

2014-01-01

Climate change affects both habitat suitability and the genetic diversity of wild plants. Therefore, predicting and establishing the most effective and coherent conservation areas is essential for the conservation of genetic diversity in response to climate change. This is because genetic variance is a product not only of habitat suitability in conservation areas but also of efficient protection and management. Phellodendron amurense Rupr. is a tree species (family Rutaceae) that is endangered due to excessive and illegal harvesting for use in Chinese medicine. Here, we test a general computational method for the prediction of priority conservation areas (PCAs) by measuring the genetic diversity of P. amurense across the entirety of northeast China using a single strand repeat analysis of twenty microsatellite markers. Using computational modeling, we evaluated the geographical distribution of the species, both now and in different future climate change scenarios. Different populations were analyzed according to genetic diversity, and PCAs were identified using a spatial conservation prioritization framework. These conservation areas were optimized to account for the geographical distribution of P. amurense both now and in the future, to effectively promote gene flow, and to have a long period of validity. In situ and ex situ conservation, strategies for vulnerable populations were proposed. Three populations with low genetic diversity are predicted to be negatively affected by climate change, making conservation of genetic diversity challenging due to decreasing habitat suitability. Habitat suitability was important for the assessment of genetic variability in existing nature reserves, which were found to be much smaller than the proposed PCAs. Finally, a simple set of conservation measures was established through modeling. This combined molecular and computational ecology approach provides a framework for planning the protection of species endangered by climate change. PMID:25165526

Gene panel testing for hereditary breast cancer.

PubMed

Winship, Ingrid; Southey, Melissa C

2016-03-21

Inherited predisposition to breast cancer is explained only in part by mutations in the BRCA1 and BRCA2 genes. Most families with an apparent familial clustering of breast cancer who are investigated through Australia's network of genetic services and familial cancer centres do not have mutations in either of these genes. More recently, additional breast cancer predisposition genes, such as PALB2, have been identified. New genetic technology allows a panel of multiple genes to be tested for mutations in a single test. This enables more women and their families to have risk assessment and risk management, in a preventive approach to predictable breast cancer. Predictive testing for a known family-specific mutation in a breast cancer predisposition gene provides personalised risk assessment and evidence-based risk management. Breast cancer predisposition gene panel tests have a greater diagnostic yield than conventional testing of only the BRCA1 and BRCA2 genes. The clinical validity and utility of some of the putative breast cancer predisposition genes is not yet clear. Ethical issues warrant consideration, as multiple gene panel testing has the potential to identify secondary findings not originally sought by the test requested. Multiple gene panel tests may provide an affordable and effective way to investigate the heritability of breast cancer.

Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles.

PubMed

McDermott, Kirstie L; McFall, G Peggy; Andrews, Shea J; Anstey, Kaarin J; Dixon, Roger A

2017-10-01

Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimer's disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genetic diversity predicts pathogen resistance and cell-mediated immunocompetence in house finches

PubMed Central

Hawley, Dana M; Sydenstricker, Keila V; Kollias, George V; Dhondt, André A

2005-01-01

Evidence is accumulating that genetic variation within individual hosts can influence their susceptibility to pathogens. However, there have been few opportunities to experimentally test this relationship, particularly within outbred populations of non-domestic vertebrates. We performed a standardized pathogen challenge in house finches (Carpodacus mexicanus) to test whether multilocus heterozygosity across 12 microsatellite loci predicts resistance to a recently emerged strain of the bacterial pathogen, Mycoplasma gallisepticum (MG). We simultaneously tested whether the relationship between heterozygosity and pathogen susceptibility is mediated by differences in cell-mediated or humoral immunocompetence. We inoculated 40 house finches with MG under identical conditions and assayed both humoral and cell-mediated components of the immune response. Heterozygous house finches developed less severe disease when infected with MG, and they mounted stronger cell-mediated immune responses to phytohaemagglutinin. Differences in cell-mediated immunocompetence may, therefore, partly explain why more heterozygous house finches show greater resistance to MG. Overall, our results underscore the importance of multilocus heterozygosity for individual pathogen resistance and immunity. PMID:17148199

Steroid-resistant nephrotic syndrome: impact of genetic testing.

PubMed

Kari, Jameela A; El-Desoky, Sherif M; Gari, Mamdooh; Malik, Khalid; Vega-Warner, Virginia; Lovric, Svjetlana; Bockenhauer, Detlef

2013-01-01

Mutations in several genes are known to cause steroid-resistant nephrotic syndome (SRNS), most commonly in NPHS1, NPHS2, and WT1. Our aims were to determine the frequency of mutations in these genes in children with SRNS, the response of patients with SRNS to various immunosuppressants, and the disease outcome, and to review the predictive value of genetic testing and renal biopsy result. A retrospective review was performed of the medical records for all children with SRNS who were treated and followed-up in the Pediatric Nephrology Unit of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia from 2002-2012. We retrospectively reviewed the medical records of children above 1 year of age, who presented with SRNS to KAUH, Jeddah, Saudi Arabia, in the 10-year interval from 2002-2012 and for whom the results of genetic testing for NPHS1, NPHS2, and WT1 were available. We compared the clinical phenotype, including response to treatment and renal outcome to genotype data. We identified 44 children with a clinical diagnosis of SRNS in whom results of genetic testing were available. Presumably disease-causing mutations were detected in 5 children (11.4%) of which 3 (6.8%) had NPHS2 mutation and 2 (4.5%) had NPHS1 mutation. Renal biopsy revealed minimal change disease (MCD) or variants in 17 children, focal segmental glomerulosclerosis (FSGS) in 23 children, membranoproliferative changes (MPGN) in 2 children, and IgA nephropathy in another 2 children. Children with MCD on biopsy were more likely to respond to treatment than those with FSGS. None of those with an identified genetic cause showed any response to treatment. The frequency of identified disease-causing mutations in children older than 1 year with SRNS presented to KAUH was 11.4%, and these patients showed no response to treatment. Initial testing for gene mutation in children with SRNS may obviate the need for biopsy, and the use of immunosuppressive treatment in children with disease due to NPHS1 or NPHS2 mutations. Renal biopsy was useful in predicting response in those without genetic mutations.

Personal genome testing: Test characteristics to clarify the discourse on ethical, legal and societal issues

PubMed Central

2011-01-01

Background As genetics technology proceeds, practices of genetic testing have become more heterogeneous: many different types of tests are finding their way to the public in different settings and for a variety of purposes. This diversification is relevant to the discourse on ethical, legal and societal issues (ELSI) surrounding genetic testing, which must evolve to encompass these differences. One important development is the rise of personal genome testing on the basis of genetic profiling: the testing of multiple genetic variants simultaneously for the prediction of common multifactorial diseases. Currently, an increasing number of companies are offering personal genome tests directly to consumers and are spurring ELSI-discussions, which stand in need of clarification. This paper presents a systematic approach to the ELSI-evaluation of personal genome testing for multifactorial diseases along the lines of its test characteristics. Discussion This paper addresses four test characteristics of personal genome testing: its being a non-targeted type of testing, its high analytical validity, low clinical validity and problematic clinical utility. These characteristics raise their own specific ELSI, for example: non-targeted genetic profiling poses serious problems for information provision and informed consent. Questions about the quantity and quality of the necessary information, as well as about moral responsibilities with regard to the provision of information are therefore becoming central themes within ELSI-discussions of personal genome testing. Further, the current low level of clinical validity of genetic profiles raises questions concerning societal risks and regulatory requirements, whereas simultaneously it causes traditional ELSI-issues of clinical genetics, such as psychological and health risks, discrimination, and stigmatization, to lose part of their relevance. Also, classic notions of clinical utility are challenged by the newer notion of 'personal utility.' Summary Consideration of test characteristics is essential to any valuable discourse on the ELSI of personal genome testing for multifactorial diseases. Four key characteristics of the test - targeted/non-targeted testing, analytical validity, clinical validity and clinical utility - together determine the applicability and the relevance of ELSI to specific tests. The paper identifies and discusses four areas of interest for the ELSI-debate on personal genome testing: informational problems, risks, regulatory issues, and the notion of personal utility. PMID:21672210

Genetic variability in residual feed intake in rainbow trout clones and testing of indirect selection criteria (Open Access publication).

PubMed

Grima, Laure; Quillet, Edwige; Boujard, Thierry; Robert-Granié, Christèle; Chatain, Béatrice; Mambrini, Muriel

2008-01-01

Little is known about the genetic basis of residual feed intake (RFI) variation in fish, since this trait is highly sensitive to environmental influences, and feed intake of individuals is difficult to measure accurately. The purpose of this work was (i) to assess the genetic variability of RFI estimated by an X-ray technique and (ii) to develop predictive criteria for RFI. Two predictive criteria were tested: loss of body weight during feed deprivation and compensatory growth during re-feeding. Ten heterozygous rainbow trout clones were used. Individual intake and body weight were measured three times at three week intervals. Then, individual body weight was recorded after two cycles of a three-week feed deprivation followed by a three-week re-feeding. The ratio of the genetic variance to the phenotypic variance was found high to moderate for growth, feed intake, and RFI (VG/VP = 0.63+/-0.11, 0.29 +/-0.11, 0.29 +/-0.09, respectively). The index that integrates performances achieved during deprivation and re-feeding periods explained 59% of RFI variations. These results provide a basis for further studies on the origin of RFI differences and show that indirect criteria are good candidates for future selective breeding programs.

Germline genetic variants with implications for disease risk and therapeutic outcomes.

PubMed

Pasternak, Amy L; Ward, Kristen M; Luzum, Jasmine A; Ellingrod, Vicki L; Hertz, Daniel L

2017-10-01

Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care. Copyright © 2017 the American Physiological Society.

Psychometric testing of the decisional conflict scale: genetic testing hereditary breast and ovarian cancer.

PubMed

Katapodi, Maria C; Munro, Michelle L; Pierce, Penny F; Williams, Reg A

2011-01-01

: Hereditary breast and ovarian cancer (HBOC) syndrome is attributed mostly to mutations in the Breast Cancer 1 and Breast Cancer 2 genes (BRCA1/2). Mutation carriers of BRCA1/2 genes have significantly higher risk for developing breast cancer compared with the general population (55%-85% vs. 12%) and for developing ovarian cancer (20%-60% vs. 1.5%). The availability of genetic testing enables mutation carriers to make informed decisions about managing their cancer risk (e.g., risk-reducing surgery). However, uptake of testing for HBOC among high-risk individuals is low, indicating the need to better understand and measure the decisional conflict associated with this process. : The aim of this study was to evaluate the reliability and validity of the modified Decisional Conflict Scale for use in decisions associated with genetic testing for HBOC. : This cross-sectional cohort study, recruited women who pursued genetic testing for HBOC in two genetic risk assessment clinics affiliated with a large comprehensive cancer center and one of their female relatives who did not pursue testing. The final sample consisted of 342 women who completed all 16 items of the Decisional Conflict Scale. The psychometric properties of the scale were assessed using tests of reliability and validity, including face, content, construct, contrast, convergent, divergent, and predictive validity. : Factor analysis using principal axis factoring with oblimin rotation elicited a three-factor structure: (a) Lack of Knowledge About the Decision (α = .97), (b) Lack of Autonomy in Decision Making (α = .94), and (c) Lack of Confidence in Decision Making (α = .87). These factors explained 82% of the variance in decisional conflict about genetic testing. Cronbach's alpha coefficient was .96. : The instrument is an important tool for researchers and healthcare providers working with women at risk for HBOC who are deciding whether genetic testing is the right choice for them.

Huntington's disease predictive testing: the case for an assessment approach to requests from adolescents.

PubMed Central

Binedell, J; Soldan, J R; Scourfield, J; Harper, P S

1996-01-01

Adolescents who are actively requesting Huntington's predictive testing of their own accord pose a dilemma to those providing testing. In the absence of empirical evidence as regards the impact of genetic testing on minors, current policy and guidelines, based on the ethical principles of non-maleficence and respect for individual autonomy and confidentiality, generally exclude the testing of minors. It is argued that adherence to an age based exclusion criterion in Huntington's disease predictive testing protocols is out of step with trends in UK case law concerning minors' consent to medical treatment. Furthermore, contributions from developmental psychology and research into adolescents' decision making competence suggest that adolescents can make informed choices about their health and personal lives. Criteria for developing an assessment approach to such requests are put forward and the implications of a case by case evaluation of competence to consent in terms of clinicians' tolerance for uncertainty are discussed. PMID:8950670

Climate as a driver of tropical insular diversity: comparative phylogeography of two ecologically distinctive frogs in Puerto Rico

PubMed Central

Barker, Brittany S.; Rodríguez-Robles, Javier A.; Cook, Joseph A.

2014-01-01

The effects of late Quaternary climate on distributions and evolutionary dynamics of insular species are poorly understood in most tropical archipelagoes. We used ecological niche models under past and current climate to derive hypotheses regarding how stable climatic conditions shaped genetic diversity in two ecologically distinctive frogs in Puerto Rico. Whereas the Mountain Coquí, Eleutherodactylus portoricensis, is restricted to montane forest in the Cayey and Luquillo Mountains, the Red-eyed Coquí, E. antillensis, is a habitat generalist distributed across the entire Puerto Rican Bank (Puerto Rico and the Virgin Islands, excluding St. Croix). To test our hypotheses, we conducted phylogeographic and population genetic analyses based on mitochondrial and nuclear loci of each species across their range in Puerto Rico. Patterns of population differentiation in E. portoricensis, but not in E. antillensis, supported our hypotheses. For E. portoricensis, these patterns include: individuals isolated by long-term unsuitable climate in the Río Grande de Loíza Basin in eastern Puerto Rico belong to different genetic clusters; past and current climate strongly predicted genetic differentiation; and Cayey and Luquillo Mountains populations split prior to the last interglacial. For E. antillensis, these patterns include: genetic clusters did not fully correspond to predicted long-term unsuitable climate; and past and current climate weakly predicted patterns of genetic differentiation. Genetic signatures in E. antillensis are consistent with a recent range expansion into western Puerto Rico, possibly resulting from climate change and anthropogenic influences. As predicted, regions with a large area of long-term suitable climate were associated with higher genetic diversity in both species, suggesting larger and more stable populations. Finally, we discussed the implications of our findings for developing evidence-based management decisions for E. portoricensis, a taxon of special concern. Our findings illustrate the role of persistent suitable climatic conditions in promoting the persistence and diversification of tropical island organisms. PMID:26508809

Climate as a driver of tropical insular diversity: comparative phylogeography of two ecologically distinctive frogs in Puerto Rico.

PubMed

Barker, Brittany S; Rodríguez-Robles, Javier A; Cook, Joseph A

2015-08-01

The effects of late Quaternary climate on distributions and evolutionary dynamics of insular species are poorly understood in most tropical archipelagoes. We used ecological niche models under past and current climate to derive hypotheses regarding how stable climatic conditions shaped genetic diversity in two ecologically distinctive frogs in Puerto Rico. Whereas the Mountain Coquí, Eleutherodactylus portoricensis , is restricted to montane forest in the Cayey and Luquillo Mountains, the Red-eyed Coquí, E. antillensis , is a habitat generalist distributed across the entire Puerto Rican Bank (Puerto Rico and the Virgin Islands, excluding St. Croix). To test our hypotheses, we conducted phylogeographic and population genetic analyses based on mitochondrial and nuclear loci of each species across their range in Puerto Rico. Patterns of population differentiation in E. portoricensis , but not in E. antillensis , supported our hypotheses. For E. portoricensis , these patterns include: individuals isolated by long-term unsuitable climate in the Río Grande de Loíza Basin in eastern Puerto Rico belong to different genetic clusters; past and current climate strongly predicted genetic differentiation; and Cayey and Luquillo Mountains populations split prior to the last interglacial. For E. antillensis , these patterns include: genetic clusters did not fully correspond to predicted long-term unsuitable climate; and past and current climate weakly predicted patterns of genetic differentiation. Genetic signatures in E. antillensis are consistent with a recent range expansion into western Puerto Rico, possibly resulting from climate change and anthropogenic influences. As predicted, regions with a large area of long-term suitable climate were associated with higher genetic diversity in both species, suggesting larger and more stable populations. Finally, we discussed the implications of our findings for developing evidence-based management decisions for E. portoricensis , a taxon of special concern. Our findings illustrate the role of persistent suitable climatic conditions in promoting the persistence and diversification of tropical island organisms.

Genetic and developmental factors in spontaneous selective attention: a study of normal twins.

PubMed

Myles-Worsley, M; Coon, H

1997-08-08

The Spontaneous Selective Attention Task (SSAT) is a visual word identification task designed to measure the type of selective attention that occurs spontaneously when there are multiple stimuli, all potentially relevant, and insufficient time to process each of them fully. These are conditions which are common in everyday life. SSAT performance is measured by word identification accuracy, first under a baseline divided attention condition with no predictability, then under a selective attention condition with partial predictability introduced via word repetition. Accuracy to identify novel words in the upper location which becomes partially predictable (P words) vs. the lower location which remains non-predictable (N words) can be used to calculate a baseline performance index and a P/N ratio measure of selective attention. The SSAT has been shown to identify an attentional abnormality that may be useful in the development of an attentional endophenotype for family-genetic studies of schizophrenia. This study examined age and genetic effects on SSAT performance in normal children in order to evaluate whether the SSAT has the potential to qualify as a candidate endophenotype for schizophrenia in studies of at-risk children. A total of 59 monozygotic twin pairs and 33 same-sex dizygotic twin pairs ranging from 10 to 18 years of age were tested on the SSAT, a Continuous Performance Test. (CPT), a Span of Apprehension Test (SPAN) and a full-scale IQ test. Baseline performance on the SSAT, which was correlated with verbal IQ and SPAN performance, improved with age but showed no significant heritability. The P/N selectivity ratio was stable over the 10-18-year age range, was not significantly correlated with IQ, CPT, or SPAN performance, and its heritability was estimated to be 0.41. These findings suggest that the P/N selectivity ratio measured by the SSAT may be useful as a vulnerability marker in studies of children born into families segregating schizophrenia.

Data Sufficiency Assessment and Pumping Test Design for Groundwater Prediction Using Decision Theory and Genetic Algorithms

NASA Astrophysics Data System (ADS)

McPhee, J.; William, Y. W.

2005-12-01

This work presents a methodology for pumping test design based on the reliability requirements of a groundwater model. Reliability requirements take into consideration the application of the model results in groundwater management, expressed in this case as a multiobjective management model. The pumping test design is formulated as a mixed-integer nonlinear programming (MINLP) problem and solved using a combination of genetic algorithm (GA) and gradient-based optimization. Bayesian decision theory provides a formal framework for assessing the influence of parameter uncertainty over the reliability of the proposed pumping test. The proposed methodology is useful for selecting a robust design that will outperform all other candidate designs under most potential 'true' states of the system

Spirituality, Illness Unpredictability, and Math Anxiety Effects on Negative Affect and Affect-Management Coping for Individuals Diagnosed with Alpha-1 Antitrypsin Deficiency.

PubMed

Worthington, Amber K; Parrott, Roxanne L; Smith, Rachel A

2018-04-01

A growing number of genetic tests are included in diagnostic protocols associated with many common conditions. A positive diagnosis associated with the presence of some gene versions in many instances predicts a range of possible outcomes, and the uncertainty linked to such results contributes to the need to understand varied responses and plan strategic communication. Uncertainty in illness theory (UIT; Mishel, 1988, 1990) guided the investigation of efforts to feel in control and hopeful regarding genetic testing and diagnosis for alpha-1 antitrypsin deficiency (AATD). Participants included 137 individuals with AATD recruited from the Alpha-1 Research Registry who were surveyed about their subjective numeracy, anxiety about math, spirituality, perceptions of illness unpredictability, negative affect regarding genetic testing, and coping strategies about a diagnosis. Results revealed that experiencing more fear and worry contributed both directly and indirectly to affect-management coping strategies, operating through individual perceptions of illness unpredictability. The inability to predict the symptoms and course of events related to a genetic illness and anxiety regarding math heightened fear and worry. Spirituality lessened both illness unpredictability and negative affective responses to a diagnosis. Results affirm the importance of clinician and counselor efforts to incorporate attention to patient spirituality. They also illustrate the complexity associated with strategic efforts to plan communication about the different versions of a gene's effects on well-being, when some versions align with mild health effects and others with severe effects.

Wildlife translocation: the conservation implications of pathogen exposure and genetic heterozygosity

PubMed Central

2011-01-01

Background A key challenge for conservation biologists is to determine the most appropriate demographic and genetic management strategies for wildlife populations threatened by disease. We explored this topic by examining whether genetic background and previous pathogen exposure influenced survival of translocated animals when captive-bred and free-ranging bighorn sheep (Ovis canadensis) were used to re-establish a population that had been extirpated in the San Andres Mountains in New Mexico, USA. Results Although the free-ranging source population had significantly higher multi-locus heterozygosity at 30 microsatellite loci than the captive bred animals, neither source population nor genetic background significantly influenced survival or cause of death. The presence of antibodies to a respiratory virus known to cause pneumonia was associated with increased survival, but there was no correlation between genetic heterozygosity and the presence of antibodies to this virus. Conclusions Although genetic theory predicts otherwise, increased heterozygosity was not associated with increased fitness (survival) among translocated animals. While heterosis or genetic rescue effects may occur in F1 and later generations as the two source populations interbreed, we conclude that previous pathogen exposure was a more important marker than genetic heterozygosity for predicting survival of translocated animals. Every wildlife translocation is an experiment, and whenever possible, translocations should be designed and evaluated to test hypotheses that will further improve our understanding of how pathogen exposure and genetic variability influence fitness. PMID:21284886

Wildlife translocation: the conservation implications of pathogen exposure and genetic heterozygosity.

PubMed

Boyce, Walter M; Weisenberger, Mara E; Penedo, M Cecilia T; Johnson, Christine K

2011-02-01

A key challenge for conservation biologists is to determine the most appropriate demographic and genetic management strategies for wildlife populations threatened by disease. We explored this topic by examining whether genetic background and previous pathogen exposure influenced survival of translocated animals when captive-bred and free-ranging bighorn sheep (Ovis canadensis) were used to re-establish a population that had been extirpated in the San Andres Mountains in New Mexico, USA. Although the free-ranging source population had significantly higher multi-locus heterozygosity at 30 microsatellite loci than the captive bred animals, neither source population nor genetic background significantly influenced survival or cause of death. The presence of antibodies to a respiratory virus known to cause pneumonia was associated with increased survival, but there was no correlation between genetic heterozygosity and the presence of antibodies to this virus. Although genetic theory predicts otherwise, increased heterozygosity was not associated with increased fitness (survival) among translocated animals. While heterosis or genetic rescue effects may occur in F1 and later generations as the two source populations interbreed, we conclude that previous pathogen exposure was a more important marker than genetic heterozygosity for predicting survival of translocated animals. Every wildlife translocation is an experiment, and whenever possible, translocations should be designed and evaluated to test hypotheses that will further improve our understanding of how pathogen exposure and genetic variability influence fitness.

Genes, embryos, and future people.

PubMed

Glannon, Walter

1998-07-01

Testing embryonic cells for genetic abnormalities gives us the capacity to predict whether and to what extent people will exist with disease and disability. Moreover, the freezing of embryos for long periods of time enables us to alter the length of a normal human lifespan. After highlighting the shortcomings of somatic-cell gene therapy and germ-line genetic alteration, I argue that the testing and selective termination of genetically defective embryos is the only medically and morally defensible way to prevent the existence of people with severe disability, pain and suffering that make their lives not worth living for them on the whole. In addition, I consider the possible harmful effects on children born from frozen embryos after the deaths of their biological parents, or when their parents are at an advanced age. I also explore whether embryos have moral status and whether the prospects for disease-preventing genetic alteration can justify long-term cryopreservation of embryos.

Genotype * environment interaction: a case study for Douglas-fir in western Oregon.

Treesearch

Robert K. Campbell

1992-01-01

Unrecognized genotype x environment interactions (g,e) can bias genetic-gain predictions and models for predicting growth dynamics or species perturbations by global climate change. This study tested six sets of families in 10 plantation sites in a 78-thousand-hectare breeding zone. Plantation differences accounted for 71 percent of sums of squares (15-year heights),...

The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.

PubMed

Shields, B M; McDonald, T J; Ellard, S; Campbell, M J; Hyde, C; Hattersley, A T

2012-05-01

Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual's probability of having MODY, as a crucial tool for rational genetic testing. We developed prediction models using logistic regression on data from 1,191 patients with MODY (n = 594), type 1 diabetes (n = 278) and type 2 diabetes (n = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. The models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA(1c), parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA(1c), parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis <25 years and an affected parent. The models are now available online at www.diabetesgenes.org . We have developed clinical prediction models that calculate an individual's probability of having MODY. This allows an improved and more rational approach to determine who should have molecular genetic testing.

Some legal aspects of genetic screening.

PubMed

Abbing, H R

2003-01-01

Screening activities in health care are not always useful and sometimes harmful. The mere offer of a screening test puts the individual's autonomy under constraint. With genetic (predictive and risk assessment) tests, the right to free, informed consent and to protection of privacy and medical confidentiality is even more warranted. Screening evokes many questions from the perspective of the right to health care as well as (in particular with genetic screening) from the perspective of respect for individual human rights. Fear of liability puts pressure on professional restraint not to offer every screening test available. States have to take legislative measures for guaranteeing that only those screening activities become available that can significantly contribute to individual and public health. They also should consider additional rules for protecting individual rights where those that are generally accepted in the "ordinary" medical setting (the individual patient-doctor relationship), offer insufficient protection.

Genetic constraints predict evolutionary divergence in Dalechampia blossoms.

PubMed

Bolstad, Geir H; Hansen, Thomas F; Pélabon, Christophe; Falahati-Anbaran, Mohsen; Pérez-Barrales, Rocío; Armbruster, W Scott

2014-08-19

If genetic constraints are important, then rates and direction of evolution should be related to trait evolvability. Here we use recently developed measures of evolvability to test the genetic constraint hypothesis with quantitative genetic data on floral morphology from the Neotropical vine Dalechampia scandens (Euphorbiaceae). These measures were compared against rates of evolution and patterns of divergence among 24 populations in two species in the D. scandens species complex. We found clear evidence for genetic constraints, particularly among traits that were tightly phenotypically integrated. This relationship between evolvability and evolutionary divergence is puzzling, because the estimated evolvabilities seem too large to constitute real constraints. We suggest that this paradox can be explained by a combination of weak stabilizing selection around moving adaptive optima and small realized evolvabilities relative to the observed additive genetic variance.

Genetic testing in congenital heart disease: A clinical approach

PubMed Central

Chaix, Marie A; Andelfinger, Gregor; Khairy, Paul

2016-01-01

Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel. PMID:26981213

Paleoclimatic modeling and phylogeography of least killifish, Heterandria formosa: insights into Pleistocene expansion-contraction dynamics and evolutionary history of North American Coastal Plain freshwater biota.

PubMed

Bagley, Justin C; Sandel, Michael; Travis, Joseph; Lozano-Vilano, María de Lourdes; Johnson, Jerald B

2013-10-09

Climatic and sea-level fluctuations throughout the last Pleistocene glacial cycle (~130-0 ka) profoundly influenced present-day distributions and genetic diversity of Northern Hemisphere biotas by forcing range contractions in many species during the glacial advance and allowing expansion following glacial retreat ('expansion-contraction' model). Evidence for such range dynamics and refugia in the unglaciated Gulf-Atlantic Coastal Plain stems largely from terrestrial species, and aquatic species Pleistocene responses remain relatively uninvestigated. Heterandria formosa, a wide-ranging regional endemic, presents an ideal system to test the expansion-contraction model within this biota. By integrating ecological niche modeling and phylogeography, we infer the Pleistocene history of this livebearing fish (Poeciliidae) and test for several predicted distributional and genetic effects of the last glaciation. Paleoclimatic models predicted range contraction to a single southwest Florida peninsula refugium during the Last Glacial Maximum, followed by northward expansion. We inferred spatial-population subdivision into four groups that reflect genetic barriers outside this refuge. Several other features of the genetic data were consistent with predictions derived from an expansion-contraction model: limited intraspecific divergence (e.g. mean mtDNA p-distance = 0.66%); a pattern of mtDNA diversity (mean Hd = 0.934; mean π = 0.007) consistent with rapid, recent population expansion; a lack of mtDNA isolation-by-distance; and clinal variation in allozyme diversity with higher diversity at lower latitudes near the predicted refugium. Statistical tests of mismatch distributions and coalescent simulations of the gene tree lent greater support to a scenario of post-glacial expansion and diversification from a single refugium than to any other model examined (e.g. multiple-refugia scenarios). Congruent results from diverse data indicate H. formosa fits the classic Pleistocene expansion-contraction model, even as the genetic data suggest additional ecological influences on population structure. While evidence for Plio-Pleistocene Gulf Coast vicariance is well described for many freshwater species presently codistributed with H. formosa, this species demography and diversification departs notably from this pattern. Species-specific expansion-contraction dynamics may therefore have figured more prominently in shaping Coastal Plain evolutionary history than previously thought. Our findings bolster growing appreciation for the complexity of phylogeographical structuring within North America's southern refugia, including responses of Coastal Plain freshwater biota to Pleistocene climatic fluctuations.

Comparison of Family History and SNPs for Predicting Risk of Complex Disease

PubMed Central

Do, Chuong B.; Hinds, David A.; Francke, Uta; Eriksson, Nicholas

2012-01-01

The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is presently known regarding the performance of these methods in situations where disease susceptibility depends on the cumulative contribution of multiple genetic factors of moderate or low penetrance. Using quantitative genetic theory, we develop a model for studying the predictive ability of family history and single nucleotide polymorphism (SNP)–based methods for assessing risk of polygenic disorders. We show that family history is most useful for highly common, heritable conditions (e.g., coronary artery disease), where it explains roughly 20%–30% of disease heritability, on par with the most successful SNP models based on associations discovered to date. In contrast, we find that for diseases of moderate or low frequency (e.g., Crohn disease) family history accounts for less than 4% of disease heritability, substantially lagging behind SNPs in almost all cases. These results indicate that, for a broad range of diseases, already identified SNP associations may be better predictors of risk than their family history–based counterparts, despite the large fraction of missing heritability that remains to be explained. Our model illustrates the difficulty of using either family history or SNPs for standalone disease prediction. On the other hand, we show that, unlike family history, SNP–based tests can reveal extreme likelihood ratios for a relatively large percentage of individuals, thus providing potentially valuable adjunctive evidence in a differential diagnosis. PMID:23071447

Exploring the genetic architecture and improving genomic prediction accuracy for mastitis and milk production traits in dairy cattle by mapping variants to hepatic transcriptomic regions responsive to intra-mammary infection.

PubMed

Fang, Lingzhao; Sahana, Goutam; Ma, Peipei; Su, Guosheng; Yu, Ying; Zhang, Shengli; Lund, Mogens Sandø; Sørensen, Peter

2017-05-12

A better understanding of the genetic architecture of complex traits can contribute to improve genomic prediction. We hypothesized that genomic variants associated with mastitis and milk production traits in dairy cattle are enriched in hepatic transcriptomic regions that are responsive to intra-mammary infection (IMI). Genomic markers [e.g. single nucleotide polymorphisms (SNPs)] from those regions, if included, may improve the predictive ability of a genomic model. We applied a genomic feature best linear unbiased prediction model (GFBLUP) to implement the above strategy by considering the hepatic transcriptomic regions responsive to IMI as genomic features. GFBLUP, an extension of GBLUP, includes a separate genomic effect of SNPs within a genomic feature, and allows differential weighting of the individual marker relationships in the prediction equation. Since GFBLUP is computationally intensive, we investigated whether a SNP set test could be a computationally fast way to preselect predictive genomic features. The SNP set test assesses the association between a genomic feature and a trait based on single-SNP genome-wide association studies. We applied these two approaches to mastitis and milk production traits (milk, fat and protein yield) in Holstein (HOL, n = 5056) and Jersey (JER, n = 1231) cattle. We observed that a majority of genomic features were enriched in genomic variants that were associated with mastitis and milk production traits. Compared to GBLUP, the accuracy of genomic prediction with GFBLUP was marginally improved (3.2 to 3.9%) in within-breed prediction. The highest increase (164.4%) in prediction accuracy was observed in across-breed prediction. The significance of genomic features based on the SNP set test were correlated with changes in prediction accuracy of GFBLUP (P < 0.05). GFBLUP provides a framework for integrating multiple layers of biological knowledge to provide novel insights into the biological basis of complex traits, and to improve the accuracy of genomic prediction. The SNP set test might be used as a first-step to improve GFBLUP models. Approaches like GFBLUP and SNP set test will become increasingly useful, as the functional annotations of genomes keep accumulating for a range of species and traits.

Molecular population genetics of inversion breakpoint regions in Drosophila pseudoobscura.

PubMed

Wallace, Andre G; Detweiler, Don; Schaeffer, Stephen W

2013-07-08

Paracentric inversions in populations can have a profound effect on the pattern and organization of nucleotide variability along a chromosome. Regions near inversion breakpoints are expected to have greater levels of differentiation because of reduced genetic exchange between different gene arrangements whereas central regions in the inverted segments are predicted to have lower levels of nucleotide differentiation due to greater levels of genetic flux among different karyotypes. We used the inversion polymorphism on the third chromosome of Drosophila pseudoobscura to test these predictions with an analysis of nucleotide diversity of 18 genetic markers near and away from inversion breakpoints. We tested hypotheses about how the presence of different chromosomal arrangements affects the pattern and organization of nucleotide variation. Overall, markers in the distal segment of the chromosome had greater levels of nucleotide heterozygosity than markers within the proximal segment of the chromosome. In addition, our results rejected the hypothesis that the breakpoints of derived inversions will have lower levels of nucleotide variability than breakpoints of ancestral inversions, even when strains with gene conversion events were removed. High levels of linkage disequilibrium were observed within all 11 breakpoint regions as well as between the ends of most proximal and distal breakpoints. The central region of the chromosome had the greatest levels of linkage disequilibrium compared with the proximal and distal regions because this is the region that experiences the highest level of recombination suppression. These data do not fully support the idea that genetic exchange is the sole force that influences genetic variation on inverted chromosomes.

Prenatal molecular diagnosis of oculocutaneous albinism (OCA) in a large cohort of Israeli families.

PubMed

Rosenmann, Ada; Bejarano-Achache, Idit; Eli, Dalia; Maftsir, Genia; Mizrahi-Meissonnier, Liliana; Blumenfeld, Anat

2009-10-01

To present our accumulated data on prenatal molecular diagnosis of oculocutaneous albinism (OCA) in a large cohort of Israeli albino families. Albinism consists of variable phenotypes, but only families with predicted severely handicapped albino offspring, who declared their wish to terminate a pregnancy of such a fetus, are eligible for prenatal testing. Prenatal testing is not offered otherwise. Following detailed genetic investigation and counseling, molecular prenatal testing was performed using the combination of mutation screening, direct sequencing, and haplotype analysis. A total of 55 prenatal tests were performed in 37 families; in 26 families the propositus was the child, and in 11, a parent or a close relative. In 32 families tyrosinase (TYR) mutations were diagnosed. In 5 families a P gene mutation was detected. Twelve albino fetuses were diagnosed. Following further genetic counseling, all couples elected to terminate the pregnancy. Three additional pregnancies were terminated for other reasons. Families with increased risk for an albino child with severe visual handicap, seek premarital and prenatal genetic counseling and testing, for the prevention of affected offspring. Our combined methods of molecular genetic testing enable a nationwide approach for prevention of albinism. The same paradigm can be applied to other populations affected with albinism.

Economic and developmental considerations for pharmacogenomic technology.

PubMed

Vernon, John A; Johnson, Scott J; Hughen, W Keener; Trujillo, Antonio

2006-01-01

The pharmaceutical industry's core business is the innovation, development and marketing of new drugs. Pharmacogenetic (PG) testing and technology has the potential to increase a drug's value in many ways. A critical issue for the industry is whether products in development should be teamed with genetic tests that could segment the total population into responders and non-responders. In this paper we use a cost-effectiveness framework to model the strategic decision-making considerations by pharmaceutical manufacturers as they relate to drug development and the new technology of PG (the science of using genetic markers to predict drug response). In a simple, static, one-period model we consider three drug development strategies: a drug is exclusively developed and marketed to patients with a particular genetic marker; no distinguishing among patients based on the expression of a genetic marker is made (traditional approach); and a strategy whereby a drug is marketed to patients both with and without the genetic marker but there is price discrimination between the two subpopulations. We developed three main principles: revenues under a strategy targeting only the responder subpopulation will never generate more revenue than that which could have been obtained under a traditional approach; total revenues under a targeted PG strategy will be less than that under a traditional approach but higher than a naive [corrected] view would believe them to be; and a traditional [corrected] approach will earn the same total revenues as a price discrimination strategy, assuming no intermarket arbitrage. While these principles relate to the singular (and quite narrow) consideration of drug revenues, they may nevertheless partially explain why PG is not being used as widely as was predicted several years ago when the technology first became available, especially in terms of pharmaceutical manufacturer-developed tests.

Effects of seed bank disturbance on the fine-scale genetic structure of populations of the rare shrub Grevillea macleayana.

PubMed

England, P R; Whelan, R J; Ayre, D J

2003-11-01

Dispersal in most plants is mediated by the movement of seeds and pollen, which move genes across the landscape differently. Grevillea macleayana is a rare, fire-dependent Australian shrub with large seeds lacking adaptations for dispersal; yet it produces inflorescences adapted to pollination by highly mobile vertebrates (eg birds). Interpreting fine-scale genetic structure in the light of these two processes is confounded by the recent imposition of anthropogenic disturbances with potentially contrasting genetic consequences: (1) the unusual foraging behaviour of exotic honeybees and 2. widespread disturbance of the soil-stored seedbank by road building and quarrying. To test for evidence of fine-scale genetic structure within G. macleayana populations and to test the prediction that such structure might be masked by disturbance of the seed bank, we sampled two sites in undisturbed habitat and compared their genetic structure with two sites that had been strongly affected by road building using a test for spatial autocorrelation of genotypes. High selfing levels inferred from genotypes at all four sites implies that pollen dispersal is limited. Consistent with this, we observed substantial spatial clustering of genes at 10 m or less in the two undisturbed populations and argue that this reflects the predicted effects of both high selfing levels and limited seed dispersal. In contrast, at the two sites disturbed by road building, spatial autocorrelation was weak. This suggests there has been mixing of the seed bank, counteracting the naturally low dispersal and elevated selfing due to honeybees. Pollination between near neighbours with reduced relatedness potentially has fitness consequences for G. macleayana in disturbed sites.

Female mating preferences and offspring survival: testing hypotheses on the genetic basis of mate choice in a wild lekking bird.

PubMed

Sardell, Rebecca J; Kempenaers, Bart; Duval, Emily H

2014-02-01

Indirect benefits of mate choice result from increased offspring genetic quality and may be important drivers of female behaviour. 'Good-genes-for-viability' models predict that females prefer mates of high additive genetic value, such that offspring survival should correlate with male attractiveness. Mate choice may also vary with genetic diversity (e.g. heterozygosity) or compatibility (e.g. relatedness), where the female's genotype influences choice. The relative importance of these nonexclusive hypotheses remains unclear. Leks offer an excellent opportunity to test their predictions, because lekking males provide no material benefits and choice is relatively unconstrained by social limitations. Using 12 years of data on lekking lance-tailed manakins, Chiroxiphia lanceolata, we tested whether offspring survival correlated with patterns of mate choice. Offspring recruitment weakly increased with father attractiveness (measured as reproductive success, RS), suggesting attractive males provide, if anything, only minor benefits via offspring viability. Both male RS and offspring survival until fledging increased with male heterozygosity. However, despite parent-offspring correlation in heterozygosity, offspring survival was unrelated to its own or maternal heterozygosity or to parental relatedness, suggesting survival was not enhanced by heterozygosity per se. Instead, offspring survival benefits may reflect inheritance of specific alleles or nongenetic effects. Although inbreeding depression in male RS should select for inbreeding avoidance, mates were not less related than expected under random mating. Although mate heterozygosity and relatedness were correlated, selection on mate choice for heterozygosity appeared stronger than that for relatedness and may be the primary mechanism maintaining genetic variation in this system despite directional sexual selection. © 2014 John Wiley & Sons Ltd.

Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model.

PubMed

Lee, Andrew J; Cunningham, Alex P; Tischkowitz, Marc; Simard, Jacques; Pharoah, Paul D; Easton, Douglas F; Antoniou, Antonis C

2016-12-01

The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM. The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods. The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).Genet Med 18 12, 1190-1198.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.

PubMed

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications

PubMed Central

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype–phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, ‘real-world’ experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines. PMID:29176389

To test, or not to test: time for a MODY calculator?

PubMed

Njølstad, P R; Molven, A

2012-05-01

To test, or not to test, that is often the question in diabetes genetics. This is why the paper of Shields et al in the current issue of Diabetologia is so warmly welcomed. MODY is the most common form of monogenic diabetes. Nevertheless, the optimal way of identifying MODY families still poses a challenge both for researchers and clinicians. Hattersley's group in Exeter, UK, have developed an easy-to-use MODY prediction model that can help to identify cases appropriate for genetic testing. By answering eight simple questions on the internet ( www.diabetesgenes.org/content/mody-probability-calculator ), the doctor receives a positive predictive value in return: the probability that the patient has MODY. Thus, the classical binary (yes/no) assessment provided by clinical diagnostic criteria has been substituted by a more rational, quantitative estimate. The model appears to discriminate well between MODY and type 1 and type 2 diabetes when diabetes is diagnosed before the age of 35 years. However, the performance of the MODY probability calculator should now be validated in other settings than where it was developed-and, as always, there is room for some improvements and modifications.

A quantitative test of population genetics using spatiogenetic patterns in bacterial colonies.

PubMed

Korolev, Kirill S; Xavier, João B; Nelson, David R; Foster, Kevin R

2011-10-01

It is widely accepted that population-genetics theory is the cornerstone of evolutionary analyses. Empirical tests of the theory, however, are challenging because of the complex relationships between space, dispersal, and evolution. Critically, we lack quantitative validation of the spatial models of population genetics. Here we combine analytics, on- and off-lattice simulations, and experiments with bacteria to perform quantitative tests of the theory. We study two bacterial species, the gut microbe Escherichia coli and the opportunistic pathogen Pseudomonas aeruginosa, and show that spatiogenetic patterns in colony biofilms of both species are accurately described by an extension of the one-dimensional stepping-stone model. We use one empirical measure, genetic diversity at the colony periphery, to parameterize our models and show that we can then accurately predict another key variable: the degree of short-range cell migration along an edge. Moreover, the model allows us to estimate other key parameters, including effective population size (density) at the expansion frontier. While our experimental system is a simplification of natural microbial community, we argue that it constitutes proof of principle that the spatial models of population genetics can quantitatively capture organismal evolution.

Mating tactics determine patterns of condition dependence in a dimorphic horned beetle.

PubMed

Knell, Robert J; Simmons, Leigh W

2010-08-07

The persistence of genetic variability in performance traits such as strength is surprising given the directional selection that such traits experience, which should cause the fixation of the best genetic variants. One possible explanation is 'genic capture' which is usually considered as a candidate mechanism for the maintenance of high genetic variability in sexual signalling traits. This states that if a trait is 'condition dependent', with expression being strongly influenced by the bearer's overall viability, then genetic variability can be maintained via mutation-selection balance. Using a species of dimorphic beetle with males that gain matings either by fighting or by 'sneaking', we tested the prediction of strong condition dependence for strength, walking speed and testes mass. Strength was strongly condition dependent only in those beetles that fight for access to females. Walking speed, with less of an obvious selective advantage, showed no condition dependence, and testes mass was more condition dependent in sneaks, which engage in higher levels of sperm competition. Within a species, therefore, condition dependent expression varies between morphs, and corresponds to the specific selection pressures experienced by that morph. These results support genic capture as a general explanation for the maintenance of genetic variability in traits under directional selection.

Comparison between genetic parameters of cheese yield and nutrient recovery or whey loss traits measured from individual model cheese-making methods or predicted from unprocessed bovine milk samples using Fourier-transform infrared spectroscopy.

PubMed

Bittante, G; Ferragina, A; Cipolat-Gotet, C; Cecchinato, A

2014-10-01

Cheese yield is an important technological trait in the dairy industry. The aim of this study was to infer the genetic parameters of some cheese yield-related traits predicted using Fourier-transform infrared (FTIR) spectral analysis and compare the results with those obtained using an individual model cheese-producing procedure. A total of 1,264 model cheeses were produced using 1,500-mL milk samples collected from individual Brown Swiss cows, and individual measurements were taken for 10 traits: 3 cheese yield traits (fresh curd, curd total solids, and curd water as a percent of the weight of the processed milk), 4 milk nutrient recovery traits (fat, protein, total solids, and energy of the curd as a percent of the same nutrient in the processed milk), and 3 daily cheese production traits per cow (fresh curd, total solids, and water weight of the curd). Each unprocessed milk sample was analyzed using a MilkoScan FT6000 (Foss, Hillerød, Denmark) over the spectral range, from 5,000 to 900 wavenumber × cm(-1). The FTIR spectrum-based prediction models for the previously mentioned traits were developed using modified partial least-square regression. Cross-validation of the whole data set yielded coefficients of determination between the predicted and measured values in cross-validation of 0.65 to 0.95 for all traits, except for the recovery of fat (0.41). A 3-fold external validation was also used, in which the available data were partitioned into 2 subsets: a training set (one-third of the herds) and a testing set (two-thirds). The training set was used to develop calibration equations, whereas the testing subsets were used for external validation of the calibration equations and to estimate the heritabilities and genetic correlations of the measured and FTIR-predicted phenotypes. The coefficients of determination between the predicted and measured values in cross-validation results obtained from the training sets were very similar to those obtained from the whole data set, but the coefficient of determination of validation values for the external validation sets were much lower for all traits (0.30 to 0.73), and particularly for fat recovery (0.05 to 0.18), for the training sets compared with the full data set. For each testing subset, the (co)variance components for the measured and FTIR-predicted phenotypes were estimated using bivariate Bayesian analyses and linear models. The intraherd heritabilities for the predicted traits obtained from our internal cross-validation using the whole data set ranged from 0.085 for daily yield of curd solids to 0.576 for protein recovery, and were similar to those obtained from the measured traits (0.079 to 0.586, respectively). The heritabilities estimated from the testing data set used for external validation were more variable but similar (on average) to the corresponding values obtained from the whole data set. Moreover, the genetic correlations between the predicted and measured traits were high in general (0.791 to 0.996), and they were always higher than the corresponding phenotypic correlations (0.383 to 0.995), especially for the external validation subset. In conclusion, we herein report that application of the cross-validation technique to the whole data set tended to overestimate the predictive ability of FTIR spectra, give more precise phenotypic predictions than the calibrations obtained using smaller data sets, and yield genetic correlations similar to those obtained from the measured traits. Collectively, our findings indicate that FTIR predictions have the potential to be used as indicator traits for the rapid and inexpensive selection of dairy populations for improvement of cheese yield, milk nutrient recovery in curd, and daily cheese production per cow. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

The genetics of hyperuricaemia and gout

PubMed Central

Reginato, Anthony M.; Mount, David B.; Yang, Irene; Choi, Hyon K.

2013-01-01

Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This Review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular–metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B*5801 alleles could be used to predict these potentially fatal adverse effects. PMID:22945592

Critical Need for Family-Based, Quasi-Experimental Designs in Integrating Genetic and Social Science Research

PubMed Central

Lahey, Benjamin B.; Turkheimer, Eric; Lichtenstein, Paul

2013-01-01

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene–environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles. PMID:23927516

Critical need for family-based, quasi-experimental designs in integrating genetic and social science research.

PubMed

D'Onofrio, Brian M; Lahey, Benjamin B; Turkheimer, Eric; Lichtenstein, Paul

2013-10-01

Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.

Does morality have a biological basis? An empirical test of the factors governing moral sentiments relating to incest.

PubMed

Lieberman, Debra; Tooby, John; Cosmides, Leda

2003-04-22

Kin-recognition systems have been hypothesized to exist in humans, and adaptively to regulate altruism and incest avoidance among close genetic kin. This latter function allows the architecture of the kin recognition system to be mapped by quantitatively matching individual variation in opposition to incest to individual variation in developmental parameters, such as family structure and co-residence patterns. Methodological difficulties that appear when subjects are asked to disclose incestuous inclinations can be circumvented by measuring their opposition to incest in third parties, i.e. morality. This method allows a direct test of Westermarck's original hypothesis that childhood co-residence with an opposite-sex individual predicts the strength of moral sentiments regarding third-party sibling incest. Results support Westermarck's hypothesis and the model of kin recognition that it implies. Co-residence duration objectively predicts genetic relatedness, making it a reliable cue to kinship. Co-residence duration predicts the strength of opposition to incest, even after controlling for relatedness and even when co-residing individuals are genetically unrelated. This undercuts kin-recognition models requiring matching to self (through, for example, major histocompatibility complex or phenotypic markers). Subjects' beliefs about relatedness had no effect after controlling for co-residence, indicating that systems regulating kin-relevant behaviours are non-conscious, and calibrated by co-residence, not belief.

Does morality have a biological basis? An empirical test of the factors governing moral sentiments relating to incest.

PubMed Central

Lieberman, Debra; Tooby, John; Cosmides, Leda

2003-01-01

Kin-recognition systems have been hypothesized to exist in humans, and adaptively to regulate altruism and incest avoidance among close genetic kin. This latter function allows the architecture of the kin recognition system to be mapped by quantitatively matching individual variation in opposition to incest to individual variation in developmental parameters, such as family structure and co-residence patterns. Methodological difficulties that appear when subjects are asked to disclose incestuous inclinations can be circumvented by measuring their opposition to incest in third parties, i.e. morality. This method allows a direct test of Westermarck's original hypothesis that childhood co-residence with an opposite-sex individual predicts the strength of moral sentiments regarding third-party sibling incest. Results support Westermarck's hypothesis and the model of kin recognition that it implies. Co-residence duration objectively predicts genetic relatedness, making it a reliable cue to kinship. Co-residence duration predicts the strength of opposition to incest, even after controlling for relatedness and even when co-residing individuals are genetically unrelated. This undercuts kin-recognition models requiring matching to self (through, for example, major histocompatibility complex or phenotypic markers). Subjects' beliefs about relatedness had no effect after controlling for co-residence, indicating that systems regulating kin-relevant behaviours are non-conscious, and calibrated by co-residence, not belief. PMID:12737660

Genetic perspectives on northern population cycles: bridging the gap between theory and empirical studies.

PubMed

Norén, Karin; Angerbjörn, Anders

2014-05-01

Many key species in northern ecosystems are characterised by high-amplitude cyclic population demography. In 1924, Charles Elton described the ecology and evolution of cyclic populations in a classic paper and, since then, a major focus has been the underlying causes of population cycles. Elton hypothesised that fluctuations reduced population genetic variation and influenced the direction of selection pressures. In concordance with Elton, present theories concern the direct consequences of population cycles for genetic structure due to the processes of genetic drift and selection, but also include feedback models of genetic composition on population dynamics. Most of these theories gained mathematical support during the 1970s and onwards, but due to methodological drawbacks, difficulties in long-term sampling and a complex interplay between microevolutionary processes, clear empirical data allowing the testing of these predictions are still scarce. Current genetic tools allow for estimates of genetic variation and identification of adaptive genomic regions, making this an ideal time to revisit this subject. Herein, we attempt to contribute towards a consensus regarding the enigma described by Elton almost 90 years ago. We present nine predictions covering the direct and genetic feedback consequences of population cycles on genetic variation and population structure, and review the empirical evidence. Generally, empirical support for the predictions was low and scattered, with obvious gaps in the understanding of basic population processes. We conclude that genetic variation in northern cyclic populations generally is high and that the geographic distribution and amount of diversity are usually suggested to be determined by various forms of context- and density-dependent dispersal exceeding the impact of genetic drift. Furthermore, we found few clear signatures of selection determining genetic composition in cyclic populations. Dispersal is assumed to have a strong impact on genetic structuring and we suggest that the signatures of other microevolutionary processes such as genetic drift and selection are weaker and have been over-shadowed by density-dependent dispersal. We emphasise that basic biological and demographical questions still need to be answered and stress the importance of extensive sampling, appropriate choice of tools and the value of standardised protocols. © 2013 The Authors. Biological Reviews © 2013 Cambridge Philosophical Society.

Genome-Wide Polygenic Scores Predict Reading Performance throughout the School Years

ERIC Educational Resources Information Center

Selzam, Saskia; Dale, Philip S.; Wagner, Richard K.; DeFries, John C.; Cederlöf, Martin; O'Reilly, Paul F.; Krapohl, Eva; Plomin, Robert

2017-01-01

It is now possible to create individual-specific genetic scores, called genome-wide polygenic scores (GPS). We used a GPS for years of education ("EduYears") to predict reading performance assessed at UK National Curriculum Key Stages 1 (age 7), 2 (age 12) and 3 (age 14) and on reading tests administered at ages 7 and 12 in a UK sample…

Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population.

PubMed

Paziewska, Agnieszka; Cukrowska, Bozena; Dabrowska, Michalina; Goryca, Krzysztof; Piatkowska, Magdalena; Kluska, Anna; Mikula, Michal; Karczmarski, Jakub; Oralewska, Beata; Rybak, Anna; Socha, Jerzy; Balabas, Aneta; Zeber-Lubecka, Natalia; Ambrozkiewicz, Filip; Konopka, Ewa; Trojanowska, Ilona; Zagroba, Malgorzata; Szperl, Malgorzata; Ostrowski, Jerzy

2015-01-01

Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. DNA samples of 336 CD and 264 unrelated healthy controls were used to create DNA pools for a genome wide association study (GWAS). GWAS findings were validated with individual HLA tag single nucleotide polymorphism (SNP) typing of 473 patients and 714 healthy controls. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8) were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC) region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1) and rs3130484 (HLA-independent; mapped to MSH5). Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%. This study confirmed that improvement of CD risk prediction sensitivity could be achieved by including non-HLA SNPs alongside HLA SNPs in genetic testing.

Molecular alterations and biomarkers in colorectal cancer

PubMed Central

Grady, William M.; Pritchard, Colin C.

2013-01-01

The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer genetics is leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers). PMID:24178577

A cognitive characterization of dyscalculia in Turner syndrome.

PubMed

Bruandet, Marie; Molko, Nicolas; Cohen, Laurent; Dehaene, Stanislas

2004-01-01

Current theories of number processing postulate that the human abilities for arithmetic are based on cerebral circuits that are partially laid down under genetic control and later modified by schooling and education. This view predicts the existence of genetic diseases that interfere specifically with components of the number system. Here, we investigate whether Turner syndrome (TS) corresponds to this definition. TS is a genetic disorder which affects one woman in 2500 and is characterized by partial or complete absence of one X chromosome. In addition to well-characterized physical and hormonal dysfunction, TS patients exhibit cognitive deficits including dyscalculia. We tested 12 women with Turner syndrome and 13 control subjects on a cognitive battery including arithmetical tests (addition, subtraction, multiplication, division) as well as tests of the understanding of numerosity and quantity (cognitive estimation, estimation, comparison, bisection, subitizing/counting). Impairments were observed in cognitive estimation, subitizing, and calculation. We examine whether these deficits can be attributed to a single source, and discuss the possible implications of hormonal and genetic factors in the neuropsychological profile of TS patients.

Modeling of genetic gain for single traits from marker-assisted seedling selection in clonally propagated crops

PubMed Central

Ru, Sushan; Hardner, Craig; Carter, Patrick A; Evans, Kate; Main, Dorrie; Peace, Cameron

2016-01-01

Seedling selection identifies superior seedlings as candidate cultivars based on predicted genetic potential for traits of interest. Traditionally, genetic potential is determined by phenotypic evaluation. With the availability of DNA tests for some agronomically important traits, breeders have the opportunity to include DNA information in their seedling selection operations—known as marker-assisted seedling selection. A major challenge in deploying marker-assisted seedling selection in clonally propagated crops is a lack of knowledge in genetic gain achievable from alternative strategies. Existing models based on additive effects considering seed-propagated crops are not directly relevant for seedling selection of clonally propagated crops, as clonal propagation captures all genetic effects, not just additive. This study modeled genetic gain from traditional and various marker-based seedling selection strategies on a single trait basis through analytical derivation and stochastic simulation, based on a generalized seedling selection scheme of clonally propagated crops. Various trait-test scenarios with a range of broad-sense heritability and proportion of genotypic variance explained by DNA markers were simulated for two populations with different segregation patterns. Both derived and simulated results indicated that marker-based strategies tended to achieve higher genetic gain than phenotypic seedling selection for a trait where the proportion of genotypic variance explained by marker information was greater than the broad-sense heritability. Results from this study provides guidance in optimizing genetic gain from seedling selection for single traits where DNA tests providing marker information are available. PMID:27148453

Initiation of reflective frames in counseling for Huntingtons Disease predictive testing.

PubMed

Sarangi, Srikant; Bennert, Kristina; Howell, Lucy; Clarke, Angus; Harper, Peter; Gray, Jonathon

2004-04-01

Genetic professionals and clients are likely to assign different meanings to the extended format of the counseling protocols for predictive testing. In order to facilitate informed, client-centered decisions about the possibility of predictive testing, counselors routinely use the question format to initiate what we call "reflective frames" that invite clients to discuss their feelings and encourage them to adopt introspective and self-reflective stances toward their own experience--spanning the past, the present, and the hypothetical future. We suggest that such initiations of reflective frames constitute a key element of counselors' nondirective stance, although the exact nature of their formulations can be complex and varied. Examining 24 Huntington's Disease (HD) clinic sessions involving 12 families in South Wales with the tools of discourse analysis, our focus in this paper is twofold: (i) to propose a classification of six types of reflective questions (e.g. nonspecific invites, awareness and anxiety, decision about testing, impact of result, dissemination, and other) and to examine their distribution across the various clinic appointments, and (ii) to investigate the scope of these questions in terms of temporal and social axes. We link our analysis to the current debate within the genetic counseling profession about the merits of reflection- versus information-focused counseling styles and the need to abide by professionally warranted and institutionally embedded counseling protocols.

Molecular Diagnostics in Colorectal Carcinoma: Advances and Applications for 2018.

PubMed

Bhalla, Amarpreet; Zulfiqar, Muhammad; Bluth, Martin H

2018-06-01

The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis. Mismatch repair-deficient tumors have higher rates of programmed death-ligand 1 expression. Cell-free DNA analysis in fluids are proving beneficial for diagnosis and prognosis in these disease states towards effective patient management. Copyright © 2018 Elsevier Inc. All rights reserved.

Mutagenicity of fractionated test material from the synthetic fuel technology with bacterial systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, T.K.; Young, J.A.; Hardigree, A.A.

1978-01-01

The predictive value of short-term genetic tests, such as the Salmonella and Escherichia coli (K-12, 343/113) systems including microsomal activation, is well documented. We have applied the short-term testing to various crude products and effluents from the synthetic fuel technologies. Class fractionation and column chromatography of the test materials and the coupled bioassays can be used to identify the most active fractions (collaborative effort with Analytical Chemistry Division). Reversion at the histidine locus for Salmonella was assayed with each fraction and the results are expressed in units of revertants (strain TA98) per milligram of the starting material (organic content) includingmore » metabolic activation with a crude rat liver preparation. Results obtained with the Salmonella system were validated by employing E. coli strains auxotrophic for arginine. Genetic activity is seen with a variety of fractions, largely the basic and neutral (PAH) components. Total activity varies from process to process, thus, the short-term genetic test can be considered a useful prescreen for potential biohazard of various effluents both in plants and in the immediate plant environment.« less

Genetic constraints predict evolutionary divergence in Dalechampia blossoms

PubMed Central

Bolstad, Geir H.; Hansen, Thomas F.; Pélabon, Christophe; Falahati-Anbaran, Mohsen; Pérez-Barrales, Rocío; Armbruster, W. Scott

2014-01-01

If genetic constraints are important, then rates and direction of evolution should be related to trait evolvability. Here we use recently developed measures of evolvability to test the genetic constraint hypothesis with quantitative genetic data on floral morphology from the Neotropical vine Dalechampia scandens (Euphorbiaceae). These measures were compared against rates of evolution and patterns of divergence among 24 populations in two species in the D. scandens species complex. We found clear evidence for genetic constraints, particularly among traits that were tightly phenotypically integrated. This relationship between evolvability and evolutionary divergence is puzzling, because the estimated evolvabilities seem too large to constitute real constraints. We suggest that this paradox can be explained by a combination of weak stabilizing selection around moving adaptive optima and small realized evolvabilities relative to the observed additive genetic variance. PMID:25002700

Context-sensitive network-based disease genetics prediction and its implications in drug discovery

PubMed Central

Chen, Yang; Xu, Rong

2017-01-01

Abstract Motivation: Disease phenotype networks play an important role in computational approaches to identifying new disease-gene associations. Current disease phenotype networks often model disease relationships based on pairwise similarities, therefore ignore the specific context on how two diseases are connected. In this study, we propose a new strategy to model disease associations using context-sensitive networks (CSNs). We developed a CSN-based phenome-driven approach for disease genetics prediction, and investigated the translational potential of the predicted genes in drug discovery. Results: We constructed CSNs by directly connecting diseases with associated phenotypes. Here, we constructed two CSNs using different data sources; the two networks contain 26 790 and 13 822 nodes respectively. We integrated the CSNs with a genetic functional relationship network and predicted disease genes using a network-based ranking algorithm. For comparison, we built Similarity-Based disease Networks (SBN) using the same disease phenotype data. In a de novo cross validation for 3324 diseases, the CSN-based approach significantly increased the average rank from top 12.6 to top 8.8% for all tested genes comparing with the SBN-based approach (p

Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism.

PubMed

Xu, C; Lang-Muritano, M; Phan-Hug, F; Dwyer, A A; Sykiotis, G P; Cassatella, D; Acierno, J; Mohammadi, M; Pitteloud, N

2017-08-01

Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both <0.5 U/L), suggestive of CHH. Genetic testing identified a de novo, heterozygous mutation in fibroblast growth factor receptor 1 (FGFR1 p.L630P). L630 resides on the ATP binding cleft of the FGFR1 tyrosine kinase domain, and L630P is predicted to cause a complete loss of receptor function. Cell-based assays confirmed that L630P abolishes FGF8 signaling activity. Identification of a loss-of-function de novo FGFR1 mutation in this patient confirms the diagnosis of CHH, allowing for a timely hormonal treatment to induce pubertal development. Therefore, genetic testing can complement clinical and hormonal assessment for a timely diagnosis of CHH in childhood. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reassessing insurers' access to genetic information: genetic privacy, ignorance, and injustice.

PubMed

Feiring, Eli

2009-06-01

Many countries have imposed strict regulations on the genetic information to which insurers have access. Commentators have warned against the emerging body of legislation for different reasons. This paper demonstrates that, when confronted with the argument that genetic information should be available to insurers for health insurance underwriting purposes, one should avoid appeals to rights of genetic privacy and genetic ignorance. The principle of equality of opportunity may nevertheless warrant restrictions. A choice-based account of this principle implies that it is unfair to hold people responsible for the consequences of the genetic lottery, since we have no choice in selecting our genotype or the expression of it. However appealing, this view does not take us all the way to an adequate justification of inaccessibility of genetic information. A contractarian account, suggesting that health is a condition of opportunity and that healthcare is an essential good, seems more promising. I conclude that if or when predictive medical tests (such as genetic tests) are developed with significant actuarial value, individuals have less reason to accept as fair institutions that limit access to healthcare on the grounds of risk status. Given the assumption that a division of risk pools in accordance with a rough estimate of people's level of (genetic) risk will occur, fairness and justice favour universal health insurance based on solidarity.

Fetal alcohol spectrum disorders: gene-environment interactions, predictive biomarkers, and the relationship between structural alterations in the brain and functional outcomes.

PubMed

Reynolds, James N; Weinberg, Joanne; Clarren, Sterling; Beaulieu, Christian; Rasmussen, Carmen; Kobor, Michael; Dube, Marie-Pierre; Goldowitz, Daniel

2011-03-01

Prenatal alcohol exposure is a major, preventable cause of behavioral and cognitive deficits in children. Despite extensive research, a unique neurobehavioral profile for children affected by prenatal alcohol exposure remains elusive. A fundamental question that must be addressed is how genetic and environmental factors interact with gestational alcohol exposure to produce neurobehavioral and neurobiological deficits in children. The core objectives of the NeuroDevNet team in fetal alcohol spectrum disorders is to create an integrated research program of basic and clinical investigations that will (1) identify genetic and epigenetic modifications that may be predictive of the neurobehavioral and neurobiological dysfunctions in offspring induced by gestational alcohol exposure and (2) determine the relationship between structural alterations in the brain induced by gestational alcohol exposure and functional outcomes in offspring. The overarching hypothesis to be tested is that neurobehavioral and neurobiological dysfunctions induced by gestational alcohol exposure are correlated with the genetic background of the affected child and/or epigenetic modifications in gene expression. The identification of genetic and/or epigenetic markers that are predictive of the severity of behavioral and cognitive deficits in children affected by gestational alcohol exposure will have a profound impact on our ability to identify children at risk. Copyright © 2011 Elsevier Inc. All rights reserved.

Fetal Alcohol Spectrum Disorders: Gene-Environment Interactions, Predictive Biomarkers, and the Relationship Between Structural Alterations in the Brain and Functional Outcomes

PubMed Central

Reynolds, James N.; Weinberg, Joanne; Clarren, Sterling; Beaulieu, Christian; Rasmussen, Carmen; Kobor, Michael; Dube, Marie-Pierre; Goldowitz, Daniel

2016-01-01

Prenatal alcohol exposure is a major, preventable cause of behavioral and cognitive deficits in children. Despite extensive research, a unique neurobehavioral profile for children affected by prenatal alcohol exposure remains elusive. A fundamental question that must be addressed is how genetic and environmental factors interact with gestational alcohol exposure to produce neurobehavioral and neurobiological deficits in children. The core objectives of the NeuroDevNet team in fetal alcohol spectrum disorders is to create an integrated research program of basic and clinical investigations that will (1) identify genetic and epigenetic modifications that may be predictive of the neurobehavioral and neurobiological dysfunctions in offspring induced by gestational alcohol exposure and (2) determine the relationship between structural alterations in the brain induced by gestational alcohol exposure and functional outcomes in offspring. The overarching hypothesis to be tested is that neurobehavioral and neurobiological dysfunctions induced by gestational alcohol exposure are correlated with the genetic background of the affected child and/or epigenetic modifications in gene expression. The identification of genetic and/or epigenetic markers that are predictive of the severity of behavioral and cognitive deficits in children affected by gestational alcohol exposure will have a profound impact on our ability to identify children at risk. PMID:21575841

Metabologenomics of Phaeochromocytoma and Paraganglioma: An Integrated Approach for Personalised Biochemical and Genetic Testing

PubMed Central

Eisenhofer, Graeme; Klink, Barbara; Richter, Susan; Lenders, Jacques WM; Robledo, Mercedes

2017-01-01

The tremendous advances over the past two decades in both clinical genetics and biochemical testing of chromaffin cell tumours have led to new considerations about how these aspects of laboratory medicine can be integrated to improve diagnosis and management of affected patients. With germline mutations in 15 genes now identified to be responsible for over a third of all cases of phaeochromocytomas and paragangliomas, these tumours are recognised to have one of the richest hereditary backgrounds among all neoplasms. Depending on the mutation, tumours show distinct differences in metabolic pathways that relate to or even directly impact clinical presentation. At the same time, there has been improved understanding about how catecholamines are synthesised, stored, secreted and metabolised by chromaffin cell tumours. Although the tumours may not always secrete catecholamines it has become clear that almost all continuously produce and metabolise catecholamines. This has not only fuelled changes in laboratory medicine, but has also assisted in recognition of genotype-biochemical phenotype relationships important for diagnostics and clinical care. In particular, differences in catecholamine and energy pathway metabolomes can guide genetic testing, assist with test interpretation and provide predictions about the nature, behaviour and imaging characteristics of the tumours. Conversely, results of genetic testing are important for guiding how routine biochemical testing should be employed and interpreted in surveillance programmes for at-risk patients. In these ways there are emerging needs for modern laboratory medicine to seamlessly integrate biochemical and genetic testing into the diagnosis and management of patients with chromaffin cell tumours. PMID:29332973

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis)

PubMed Central

FUNK, W. CHRIS; LOVICH, ROBERT E.; HOHENLOHE, PAUL A.; HOFMAN, COURTNEY A.; MORRISON, SCOTT A.; SILLETT, T. SCOTT; GHALAMBOR, CAMERON K.; MALDONADO, JESUS E.; RICK, TORBEN C.; DAY, MITCH D.; POLATO, NICHOLAS R.; FITZPATRICK, SARAH W.; COONAN, TIMOTHY J.; CROOKS, KEVIN R.; DILLON, ADAM; GARCELON, DAVID K.; KING, JULIE L.; BOSER, CHRISTINA L.; GOULD, NICHOLAS; ANDELT, WILLIAM F.

2016-01-01

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of 6 subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1–89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland gray foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6–6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness, and reduced adaptive potential. PMID:26992010

Blastocentesis: a source of DNA for preimplantation genetic testing. Results from a pilot study.

PubMed

Gianaroli, Luca; Magli, M Cristina; Pomante, Alessandra; Crivello, Anna M; Cafueri, Giulia; Valerio, Marzia; Ferraretti, Anna P

2014-12-01

To investigate the presence of DNA in blastocyst fluids (BFs) and to estimate whether the chromosomal status predicted by its analysis corresponds with the ploidy condition in trophectoderm (TE) cells, the whole embryo, and that predicted by polar bodies (PBs) or blastomeres. Prospective study. In vitro fertilization unit. Seventeen couples undergoing preimplantation genetic screening with the use of array comparative genomic hybridization on PBs (n = 12) or blastomeres (n = 5). BFs and TE cells were retrieved from 51 blastocysts for separate chromosomal analysis. Presence of DNA in BFs and assessment of the corresponding chromosome condition; correlation with the results in TE cells and those predicted by the analysis done at earlier stages. DNA was detected in 39 BFs (76.5%). In 38 of 39 cases (97.4%) the ploidy condition of BFs was confirmed in TE cells, and the rate of concordance per single chromosome was 96.6% (904/936). In relation to the whole embryo, the ploidy condition corresponded in all cases with a per-chromosome concordance of 98.1%. The testing of PBs and blastomeres had 93.3% and 100% prediction of BF ploidy condition with a concordance per chromosome of 93.5% and 94%, respectively. Blastocentesis could represent an alternative source of material for chromosomal testing, because the BF is highly predictive of the embryo ploidy condition and chromosome content. Our data confirm the relevance of the oocyte and of the early-cleavage embryo in determining the ploidy condition of the resulting blastocyst. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Schizophrenia and subsequent neighborhood deprivation: revisiting the social drift hypothesis using population, twin and molecular genetic data.

PubMed

Sariaslan, A; Fazel, S; D'Onofrio, B M; Långström, N; Larsson, H; Bergen, S E; Kuja-Halkola, R; Lichtenstein, P

2016-05-03

Neighborhood influences in the etiology of schizophrenia have been emphasized in a number of systematic reviews, but causality remains uncertain. To test the social drift hypothesis, we used three complementary genetically informed Swedish cohorts. First, we used nationwide Swedish data on approximately 760 000 full- and half-sibling pairs born between 1951 and 1974 and quantitative genetic models to study genetic and environmental influences on the overlap between schizophrenia in young adulthood and subsequent residence in socioeconomically deprived neighborhoods. Schizophrenia diagnoses were ascertained using the National Patient Registry. Second, we tested the overlap between childhood psychotic experiences and neighborhood deprivation in early adulthood in the longitudinal Twin Study of Child and Adolescent Development (TCHAD; n=2960). Third, we investigated to what extent polygenic risk scores for schizophrenia predicted residence in deprived neighborhoods during late adulthood using the TwinGene sample (n=6796). Sibling data suggested that living in deprived neighborhoods was substantially heritable; 65% (95% confidence interval (95% CI): 60-71%) of the variance was attributed to genetic influences. Although the correlation between schizophrenia and neighborhood deprivation was moderate in magnitude (r=0.22; 95% CI: 0.20-0.24), it was entirely explained by genetic influences. We replicated these findings in the TCHAD sample. Moreover, the association between polygenic risk for schizophrenia and neighborhood deprivation was statistically significant (R(2)=0.15%, P=0.002). Our findings are primarily consistent with a genetic selection interpretation where genetic liability for schizophrenia also predicts subsequent residence in socioeconomically deprived neighborhoods. Previous studies may have overemphasized the relative importance of environmental influences in the social drift of schizophrenia patients. Clinical and policy interventions will therefore benefit from the future identification of potentially causal pathways between different dimensions of cognitive functions and socioeconomic trajectories derived from studies adopting family-based research designs.

Using simulation models to predict feed intake: phenotypic and genetic relationships between observed and predicted values in cattle.

PubMed

Williams, C B; Bennett, G L; Jenkins, T G; Cundiff, L V; Ferrell, C L

2006-06-01

The objectives of this study were to evaluate the accuracy of the Decision Evaluator for the Cattle Industry (DECI) and the Cornell Value Discovery System (CVDS) in predicting individual DMI and to assess the feasibility of using predicted DMI data in genetic evaluations of cattle. Observed individual animal data on the average daily DMI (OFI), ADG, and carcass measurements were obtained from postweaning records of 504 steers from 52 sires (502 with complete data). The experimental data and daily temperature and wind speed data were used as inputs to predict average daily feed DMI (kg) required (feed required; FR) for maintenance, cold stress, and ADG; maintenance and cold stress; ADG; maintenance and ADG; and maintenance alone, with CVDS (CFRmcg, CFRmc, CFRg, CFRmg, and CFRm, respectively) and DECI (DFRmcg, DFRmc, DFRg, DFRmg, and DFRm, respectively). Genetic parameters were estimated by REML using an animal model with age on test as a covariate and with genotype, age of dam, and year as fixed effects. Regression equations for observed on predicted DMI were OFI = 1.27 (SE = 0.27) + 0.83 (SE = 0.04) x CFRmcg [R2 = 0.44, residual SD (s(y.x)) = 0.669 kg/d] and OFI = 1.32 (SE = 0.22) + 0.8 (SE = 0.03) x DFRmcg (R2 = 0.53, s(y.x) = 0.612 kg/d). Heritability of OFI was 0.27 +/- 0.12, and heritabilities ranged from 0.33 +/- 0.12 to 0.41 +/- 0.13 for predicted measures of DMI. Phenotypic and genetic correlations between OFI and CFRmcg, CFRmc, CFRg, CFRmg, CFRm, DFRmcg, DFRmc, DFRg, DFRmg, and DFRm were 0.67, 0.73, 0.41, 0.63, 0.78, 0.73, 0.82, 0.45, 0.77, and 0.86 (P < 0.001 for all phenotypic correlations); and 0.95 +/- 0.07, 0.82 +/- 0.13, 0.89 +/- 0.09, 0.95 +/- 0.07, 0.91 +/- 0.09, 0.96 +/- 0.07, 0.89 +/- 0.09, 0.88 +/- 0.09, 0.96 +/- 0.06, and 0.96 +/- 0.07, respectively. Phenotypic and genetic correlations between CFRmcg and DFRmcg, CFRmc and DFRmc, CFRg and DFRg, CFRmg and DFRmg, and CFRm and DFRm were 0.98, 0.94, 0.99, 0.98, and 0.95 (P < 0.001 for all phenotypic correlations), and 0.99 +/- 0.004, 0.98 +/- 0.017, 0.99 +/- 0.004, 0.99 +/- 0.005, and 0.97 +/- 0.021, respectively. The strong genetic relationships between OFI and CFRmcg, CFRmg, DFRmcg, and DFRmg indicate that these predicted measures of DMI may be used in genetic evaluations and that DM requirements for cold stress may not be needed, thus reducing model complexity. However, high genetic correlations for final weight with OFI, CFRmcg, and DFRmcg suggest that the technology needs to be further evaluated in populations with genetic variance in feed efficiency.

The evolution of trade-offs: geographic variation in call duration and flight ability in the sand cricket, Gryllus firmus.

PubMed

Roff, D A; Crnokrak, P; Fairbairn, D J

2003-07-01

Quantitative genetic theory assumes that trade-offs are best represented by bivariate normal distributions. This theory predicts that selection will shift the trade-off function itself and not just move the mean trait values along a fixed trade-off line, as is generally assumed in optimality models. As a consequence, quantitative genetic theory predicts that the trade-off function will vary among populations in which at least one of the component traits itself varies. This prediction is tested using the trade-off between call duration and flight capability, as indexed by the mass of the dorsolateral flight muscles, in the macropterous morph of the sand cricket. We use four different populations of crickets that vary in the proportion of macropterous males (Lab = 33%, Florida = 29%, Bermuda = 72%, South Carolina = 80%). We find, as predicted, that there is significant variation in the intercept of the trade-off function but not the slope, supporting the hypothesis that trade-off functions are better represented as bivariate normal distributions rather than single lines. We also test the prediction from a quantitative genetical model of the evolution of wing dimorphism that the mean call duration of macropterous males will increase with the percentage of macropterous males in the population. This prediction is also supported. Finally, we estimate the probability of a macropterous male attracting a female, P, as a function of the relative time spent calling (P = time spent calling by macropterous male/(total time spent calling by both micropterous and macropterous male). We find that in the Lab and Florida populations the probability of a female selecting the macropterous male is equal to P, indicating that preference is due simply to relative call duration. But in the Bermuda and South Carolina populations the probability of a female selecting a macropterous male is less than P, indicating a preference for the micropterous male even after differences in call duration are accounted for.

Genomic selection models double the accuracy of predicted breeding values for bacterial cold water disease resistance compared to a traditional pedigree-based model in rainbow trout aquaculture.

PubMed

Vallejo, Roger L; Leeds, Timothy D; Gao, Guangtu; Parsons, James E; Martin, Kyle E; Evenhuis, Jason P; Fragomeni, Breno O; Wiens, Gregory D; Palti, Yniv

2017-02-01

Previously, we have shown that bacterial cold water disease (BCWD) resistance in rainbow trout can be improved using traditional family-based selection, but progress has been limited to exploiting only between-family genetic variation. Genomic selection (GS) is a new alternative that enables exploitation of within-family genetic variation. We compared three GS models [single-step genomic best linear unbiased prediction (ssGBLUP), weighted ssGBLUP (wssGBLUP), and BayesB] to predict genomic-enabled breeding values (GEBV) for BCWD resistance in a commercial rainbow trout population, and compared the accuracy of GEBV to traditional estimates of breeding values (EBV) from a pedigree-based BLUP (P-BLUP) model. We also assessed the impact of sampling design on the accuracy of GEBV predictions. For these comparisons, we used BCWD survival phenotypes recorded on 7893 fish from 102 families, of which 1473 fish from 50 families had genotypes [57 K single nucleotide polymorphism (SNP) array]. Naïve siblings of the training fish (n = 930 testing fish) were genotyped to predict their GEBV and mated to produce 138 progeny testing families. In the following generation, 9968 progeny were phenotyped to empirically assess the accuracy of GEBV predictions made on their non-phenotyped parents. The accuracy of GEBV from all tested GS models were substantially higher than the P-BLUP model EBV. The highest increase in accuracy relative to the P-BLUP model was achieved with BayesB (97.2 to 108.8%), followed by wssGBLUP at iteration 2 (94.4 to 97.1%) and 3 (88.9 to 91.2%) and ssGBLUP (83.3 to 85.3%). Reducing the training sample size to n = ~1000 had no negative impact on the accuracy (0.67 to 0.72), but with n = ~500 the accuracy dropped to 0.53 to 0.61 if the training and testing fish were full-sibs, and even substantially lower, to 0.22 to 0.25, when they were not full-sibs. Using progeny performance data, we showed that the accuracy of genomic predictions is substantially higher than estimates obtained from the traditional pedigree-based BLUP model for BCWD resistance. Overall, we found that using a much smaller training sample size compared to similar studies in livestock, GS can substantially improve the selection accuracy and genetic gains for this trait in a commercial rainbow trout breeding population.

An integrated approach to infer dynamic protein-gene interactions - A case study of the human P53 protein.

PubMed

Wang, Junbai; Wu, Qianqian; Hu, Xiaohua Tony; Tian, Tianhai

2016-11-01

Investigating the dynamics of genetic regulatory networks through high throughput experimental data, such as microarray gene expression profiles, is a very important but challenging task. One of the major hindrances in building detailed mathematical models for genetic regulation is the large number of unknown model parameters. To tackle this challenge, a new integrated method is proposed by combining a top-down approach and a bottom-up approach. First, the top-down approach uses probabilistic graphical models to predict the network structure of DNA repair pathway that is regulated by the p53 protein. Two networks are predicted, namely a network of eight genes with eight inferred interactions and an extended network of 21 genes with 17 interactions. Then, the bottom-up approach using differential equation models is developed to study the detailed genetic regulations based on either a fully connected regulatory network or a gene network obtained by the top-down approach. Model simulation error, parameter identifiability and robustness property are used as criteria to select the optimal network. Simulation results together with permutation tests of input gene network structures indicate that the prediction accuracy and robustness property of the two predicted networks using the top-down approach are better than those of the corresponding fully connected networks. In particular, the proposed approach reduces computational cost significantly for inferring model parameters. Overall, the new integrated method is a promising approach for investigating the dynamics of genetic regulation. Copyright © 2016 Elsevier Inc. All rights reserved.

A population genetic interpretation of GWAS findings for human quantitative traits

PubMed Central

Bullaughey, Kevin; Hudson, Richard R.; Sella, Guy

2018-01-01

Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes—notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10−3. PMID:29547617

The creation and evaluation of a model to simulate the probability of conception in seasonal-calving pasture-based dairy heifers.

PubMed

Fenlon, Caroline; O'Grady, Luke; Butler, Stephen; Doherty, Michael L; Dunnion, John

2017-01-01

Herd fertility in pasture-based dairy farms is a key driver of farm economics. Models for predicting nulliparous reproductive outcomes are rare, but age, genetics, weight, and BCS have been identified as factors influencing heifer conception. The aim of this study was to create a simulation model of heifer conception to service with thorough evaluation. Artificial Insemination service records from two research herds and ten commercial herds were provided to build and evaluate the models. All were managed as spring-calving pasture-based systems. The factors studied were related to age, genetics, and time of service. The data were split into training and testing sets and bootstrapping was used to train the models. Logistic regression (with and without random effects) and generalised additive modelling were selected as the model-building techniques. Two types of evaluation were used to test the predictive ability of the models: discrimination and calibration. Discrimination, which includes sensitivity, specificity, accuracy and ROC analysis, measures a model's ability to distinguish between positive and negative outcomes. Calibration measures the accuracy of the predicted probabilities with the Hosmer-Lemeshow goodness-of-fit, calibration plot and calibration error. After data cleaning and the removal of services with missing values, 1396 services remained to train the models and 597 were left for testing. Age, breed, genetic predicted transmitting ability for calving interval, month and year were significant in the multivariate models. The regression models also included an interaction between age and month. Year within herd was a random effect in the mixed regression model. Overall prediction accuracy was between 77.1% and 78.9%. All three models had very high sensitivity, but low specificity. The two regression models were very well-calibrated. The mean absolute calibration errors were all below 4%. Because the models were not adept at identifying unsuccessful services, they are not suggested for use in predicting the outcome of individual heifer services. Instead, they are useful for the comparison of services with different covariate values or as sub-models in whole-farm simulations. The mixed regression model was identified as the best model for prediction, as the random effects can be ignored and the other variables can be easily obtained or simulated.

Using Full Genomic Information to Predict Disease: Breaking Down the Barriers Between Complex and Mendelian Diseases.

PubMed

Jordan, Daniel M; Do, Ron

2018-04-11

While sequence-based genetic tests have long been available for specific loci, especially for Mendelian disease, the rapidly falling costs of genome-wide genotyping arrays, whole-exome sequencing, and whole-genome sequencing are moving us toward a future where full genomic information might inform the prognosis and treatment of a variety of diseases, including complex disease. Similarly, the availability of large populations with full genomic information has enabled new insights about the etiology and genetic architecture of complex disease. Insights from the latest generation of genomic studies suggest that our categorization of diseases as complex may conceal a wide spectrum of genetic architectures and causal mechanisms that ranges from Mendelian forms of complex disease to complex regulatory structures underlying Mendelian disease. Here, we review these insights, along with advances in the prediction of disease risk and outcomes from full genomic information. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Personalized medicine in diabetes mellitus: current opportunities and future prospects.

PubMed

Kleinberger, Jeffrey W; Pollin, Toni I

2015-06-01

Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1 and type 2 diabetes, respectively, have been identified. In addition, there is emerging evidence that some genetic variants help to predict response to treatment. Other variants confer apparent protection from diabetes or its complications and may lead to development of novel treatment approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of diabetic individuals who have monogenic diabetes (e.g., maturity-onset diabetes of the young and KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of diabetes enables personalized treatment, resulting in improved and less invasive glucose control, better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should set the stage for effective clinical translation of current genetic, pharmacogenetic, and pharmacogenomic research of more complex forms of diabetes. © 2015 New York Academy of Sciences.

Personalized medicine in diabetes mellitus: current opportunities and future prospects

PubMed Central

Kleinberger, Jeffrey W.; Pollin, Toni I.

2015-01-01

Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1 and type 2 diabetes, respectively, have been identified. Additionally, there is emerging evidence that some genetic variants help to predict response to treatment. Other variants confer apparent protection from diabetes or its complications and may lead to development of novel treatment approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of diabetic individuals who have monogenic diabetes (e.g., maturity onset diabetes of the young and KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of diabetes enables personalized treatment, resulting in improved and less invasive glucose control, better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should set the stage for effective clinical translation of current genetic, pharmacogenetic, and pharmacogenomic research of more complex forms of diabetes. PMID:25907167

Effect of genotyped cows in the reference population on the genomic evaluation of Holstein cattle.

PubMed

Uemoto, Y; Osawa, T; Saburi, J

2017-03-01

This study evaluated the dependence of reliability and prediction bias on the prediction method, the contribution of including animals (bulls or cows), and the genetic relatedness, when including genotyped cows in the progeny-tested bull reference population. We performed genomic evaluation using a Japanese Holstein population, and assessed the accuracy of genomic enhanced breeding value (GEBV) for three production traits and 13 linear conformation traits. A total of 4564 animals for production traits and 4172 animals for conformation traits were genotyped using Illumina BovineSNP50 array. Single- and multi-step methods were compared for predicting GEBV in genotyped bull-only and genotyped bull-cow reference populations. No large differences in realized reliability and regression coefficient were found between the two reference populations; however, a slight difference was found between the two methods for production traits. The accuracy of GEBV determined by single-step method increased slightly when genotyped cows were included in the bull reference population, but decreased slightly by multi-step method. A validation study was used to evaluate the accuracy of GEBV when 800 additional genotyped bulls (POPbull) or cows (POPcow) were included in the base reference population composed of 2000 genotyped bulls. The realized reliabilities of POPbull were higher than those of POPcow for all traits. For the gain of realized reliability over the base reference population, the average ratios of POPbull gain to POPcow gain for production traits and conformation traits were 2.6 and 7.2, respectively, and the ratios depended on heritabilities of the traits. For regression coefficient, no large differences were found between the results for POPbull and POPcow. Another validation study was performed to investigate the effect of genetic relatedness between cows and bulls in the reference and test populations. The effect of genetic relationship among bulls in the reference population was also assessed. The results showed that it is important to account for relatedness among bulls in the reference population. Our studies indicate that the prediction method, the contribution ratio of including animals, and genetic relatedness could affect the prediction accuracy in genomic evaluation of Holstein cattle, when including genotyped cows in the reference population.

Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.

PubMed

Wertz, J; Caspi, A; Belsky, D W; Beckley, A L; Arseneault, L; Barnes, J C; Corcoran, D L; Hogan, S; Houts, R M; Morgan, N; Odgers, C L; Prinz, J A; Sugden, K; Williams, B S; Poulton, R; Moffitt, T E

2018-05-01

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.

Novel covariance-based neutrality test of time-series data reveals asymmetries in ecological and economic systems

DOE PAGES

Washburne, Alex D.; Burby, Joshua W.; Lacker, Daniel; ...

2016-09-30

Systems as diverse as the interacting species in a community, alleles at a genetic locus, and companies in a market are characterized by competition (over resources, space, capital, etc) and adaptation. Neutral theory, built around the hypothesis that individual performance is independent of group membership, has found utility across the disciplines of ecology, population genetics, and economics, both because of the success of the neutral hypothesis in predicting system properties and because deviations from these predictions provide information about the underlying dynamics. However, most tests of neutrality are weak, based on static system properties such as species-abundance distributions or themore » number of singletons in a sample. Time-series data provide a window onto a system’s dynamics, and should furnish tests of the neutral hypothesis that are more powerful to detect deviations from neutrality and more informative about to the type of competitive asymmetry that drives the deviation. Here, we present a neutrality test for time-series data. We apply this test to several microbial time-series and financial time-series and find that most of these systems are not neutral. Our test isolates the covariance structure of neutral competition, thus facilitating further exploration of the nature of asymmetry in the covariance structure of competitive systems. Much like neutrality tests from population genetics that use relative abundance distributions have enabled researchers to scan entire genomes for genes under selection, we anticipate our time-series test will be useful for quick significance tests of neutrality across a range of ecological, economic, and sociological systems for which time-series data are available. Here, future work can use our test to categorize and compare the dynamic fingerprints of particular competitive asymmetries (frequency dependence, volatility smiles, etc) to improve forecasting and management of complex adaptive systems.« less

Novel covariance-based neutrality test of time-series data reveals asymmetries in ecological and economic systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Washburne, Alex D.; Burby, Joshua W.; Lacker, Daniel

Systems as diverse as the interacting species in a community, alleles at a genetic locus, and companies in a market are characterized by competition (over resources, space, capital, etc) and adaptation. Neutral theory, built around the hypothesis that individual performance is independent of group membership, has found utility across the disciplines of ecology, population genetics, and economics, both because of the success of the neutral hypothesis in predicting system properties and because deviations from these predictions provide information about the underlying dynamics. However, most tests of neutrality are weak, based on static system properties such as species-abundance distributions or themore » number of singletons in a sample. Time-series data provide a window onto a system’s dynamics, and should furnish tests of the neutral hypothesis that are more powerful to detect deviations from neutrality and more informative about to the type of competitive asymmetry that drives the deviation. Here, we present a neutrality test for time-series data. We apply this test to several microbial time-series and financial time-series and find that most of these systems are not neutral. Our test isolates the covariance structure of neutral competition, thus facilitating further exploration of the nature of asymmetry in the covariance structure of competitive systems. Much like neutrality tests from population genetics that use relative abundance distributions have enabled researchers to scan entire genomes for genes under selection, we anticipate our time-series test will be useful for quick significance tests of neutrality across a range of ecological, economic, and sociological systems for which time-series data are available. Here, future work can use our test to categorize and compare the dynamic fingerprints of particular competitive asymmetries (frequency dependence, volatility smiles, etc) to improve forecasting and management of complex adaptive systems.« less

Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

PubMed Central

Rosmarin, Dan; Palles, Claire; Church, David; Domingo, Enric; Jones, Angela; Johnstone, Elaine; Wang, Haitao; Love, Sharon; Julier, Patrick; Scudder, Claire; Nicholson, George; Gonzalez-Neira, Anna; Martin, Miguel; Sargent, Daniel; Green, Erin; McLeod, Howard; Zanger, Ulrich M.; Schwab, Matthias; Braun, Michael; Seymour, Matthew; Thompson, Lindsay; Lacas, Benjamin; Boige, Valérie; Ribelles, Nuria; Afzal, Shoaib; Enghusen, Henrik; Jensen, Søren Astrup; Etienne-Grimaldi, Marie-Christine; Milano, Gérard; Wadelius, Mia; Glimelius, Bengt; Garmo, Hans; Gusella, Milena; Lecomte, Thierry; Laurent-Puig, Pierre; Martinez-Balibrea, Eva; Sharma, Rohini; Garcia-Foncillas, Jesus; Kleibl, Zdenek; Morel, Alain; Pignon, Jean-Pierre; Midgley, Rachel; Kerr, David; Tomlinson, Ian

2014-01-01

Purpose Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and Methods We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10−6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens. PMID:24590654

Symbiont diversity may help coral reefs survive moderate climate change.

PubMed

Baskett, Marissa L; Gaines, Steven D; Nisbet, Roger M

2009-01-01

Given climate change, thermal stress-related mass coral-bleaching events present one of the greatest anthropogenic threats to coral reefs. While corals and their symbiotic algae may respond to future temperatures through genetic adaptation and shifts in community compositions, the climate may change too rapidly for coral response. To test this potential for response, here we develop a model of coral and symbiont ecological dynamics and symbiont evolutionary dynamics. Model results without variation in symbiont thermal tolerance predict coral reef collapse within decades under multiple future climate scenarios, consistent with previous threshold-based predictions. However, model results with genetic or community-level variation in symbiont thermal tolerance can predict coral reef persistence into the next century, provided low enough greenhouse gas emissions occur. Therefore, the level of greenhouse gas emissions will have a significant effect on the future of coral reefs, and accounting for biodiversity and biological dynamics is vital to estimating the size of this effect.

Minimizing risks: the ethics of predictive diabetes mellitus screening research in newborns.

PubMed

Ross, Lainie Friedman

2003-01-01

Type 1 diabetes mellitus is the most common metabolic disease of childhood. Two states offer newborn screening to identify children with a genetic predisposition to it. It is a voluntary test offered in conjunction with the mandatory newborn metabolic screening. There are no preventive treatments, but children discovered to be at increased risk may participate in follow-up studies to determine whether and when the child develops autoantibodies (preclinical disease) or overt diabetes. This study examined the ethics of predictive genetic research in newborns for type 1 diabetes. Prediction research has serious psychosocial implications, and research designs must account for them. The study concluded that, to minimize harm to infants and their families, (1) if the research does not incorporate a prevention strategy, studies should avoid disclosure of results; and (2) if disclosure is necessary, then the research should be restricted to newborns with an affected first-degree relative.

Mismatch repair factor MSH2-MSH3 binds and alters the conformation of branched DNA structures predicted to form during genetic recombination.

PubMed

Surtees, Jennifer A; Alani, Eric

2006-07-14

Genetic studies in Saccharomyces cerevisiae predict that the mismatch repair (MMR) factor MSH2-MSH3 binds and stabilizes branched recombination intermediates that form during single strand annealing and gene conversion. To test this model, we constructed a series of DNA substrates that are predicted to form during these recombination events. We show in an electrophoretic mobility shift assay that S. cerevisiae MSH2-MSH3 specifically binds branched DNA substrates containing 3' single-stranded DNA and that ATP stimulates its release from these substrates. Chemical footprinting analyses indicate that MSH2-MSH3 specifically binds at the double-strand/single-strand junction of branched substrates, alters its conformation and opens up the junction. Therefore, MSH2-MSH3 binding to its substrates creates a unique nucleoprotein structure that may signal downstream steps in repair that include interactions with MMR and nucleotide excision repair factors.

Use of Artificial Intelligence and Machine Learning Algorithms with Gene Expression Profiling to Predict Recurrent Nonmuscle Invasive Urothelial Carcinoma of the Bladder.

PubMed

Bartsch, Georg; Mitra, Anirban P; Mitra, Sheetal A; Almal, Arpit A; Steven, Kenneth E; Skinner, Donald G; Fry, David W; Lenehan, Peter F; Worzel, William P; Cote, Richard J

2016-02-01

Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor. Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction. The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set. Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

PubMed

Wollstein, Andreas; Walsh, Susan; Liu, Fan; Chakravarthy, Usha; Rahu, Mati; Seland, Johan H; Soubrane, Gisèle; Tomazzoli, Laura; Topouzis, Fotis; Vingerling, Johannes R; Vioque, Jesus; Böhringer, Stefan; Fletcher, Astrid E; Kayser, Manfred

2017-02-27

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour

PubMed Central

Wollstein, Andreas; Walsh, Susan; Liu, Fan; Chakravarthy, Usha; Rahu, Mati; Seland, Johan H.; Soubrane, Gisèle; Tomazzoli, Laura; Topouzis, Fotis; Vingerling, Johannes R.; Vioque, Jesus; Böhringer, Stefan; Fletcher, Astrid E.; Kayser, Manfred

2017-01-01

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing. PMID:28240252

Improved prediction of biochemical recurrence after radical prostatectomy by genetic polymorphisms.

PubMed

Morote, Juan; Del Amo, Jokin; Borque, Angel; Ars, Elisabet; Hernández, Carlos; Herranz, Felipe; Arruza, Antonio; Llarena, Roberto; Planas, Jacques; Viso, María J; Palou, Joan; Raventós, Carles X; Tejedor, Diego; Artieda, Marta; Simón, Laureano; Martínez, Antonio; Rioja, Luis A

2010-08-01

Single nucleotide polymorphisms are inherited genetic variations that can predispose or protect individuals against clinical events. We hypothesized that single nucleotide polymorphism profiling may improve the prediction of biochemical recurrence after radical prostatectomy. We performed a retrospective, multi-institutional study of 703 patients treated with radical prostatectomy for clinically localized prostate cancer who had at least 5 years of followup after surgery. All patients were genotyped for 83 prostate cancer related single nucleotide polymorphisms using a low density oligonucleotide microarray. Baseline clinicopathological variables and single nucleotide polymorphisms were analyzed to predict biochemical recurrence within 5 years using stepwise logistic regression. Discrimination was measured by ROC curve AUC, specificity, sensitivity, predictive values, net reclassification improvement and integrated discrimination index. The overall biochemical recurrence rate was 35%. The model with the best fit combined 8 covariates, including the 5 clinicopathological variables prostate specific antigen, Gleason score, pathological stage, lymph node involvement and margin status, and 3 single nucleotide polymorphisms at the KLK2, SULT1A1 and TLR4 genes. Model predictive power was defined by 80% positive predictive value, 74% negative predictive value and an AUC of 0.78. The model based on clinicopathological variables plus single nucleotide polymorphisms showed significant improvement over the model without single nucleotide polymorphisms, as indicated by 23.3% net reclassification improvement (p = 0.003), integrated discrimination index (p <0.001) and likelihood ratio test (p <0.001). Internal validation proved model robustness (bootstrap corrected AUC 0.78, range 0.74 to 0.82). The calibration plot showed close agreement between biochemical recurrence observed and predicted probabilities. Predicting biochemical recurrence after radical prostatectomy based on clinicopathological data can be significantly improved by including patient genetic information. Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Evaluation of correlation between CT image features and ERCC1 protein expression in assessing lung cancer prognosis

NASA Astrophysics Data System (ADS)

Tan, Maxine; Emaminejad, Nastaran; Qian, Wei; Sun, Shenshen; Kang, Yan; Guan, Yubao; Lure, Fleming; Zheng, Bin

2014-03-01

Stage I non-small-cell lung cancers (NSCLC) usually have favorable prognosis. However, high percentage of NSCLC patients have cancer relapse after surgery. Accurately predicting cancer prognosis is important to optimally treat and manage the patients to minimize the risk of cancer relapse. Studies have shown that an excision repair crosscomplementing 1 (ERCC1) gene was a potentially useful genetic biomarker to predict prognosis of NSCLC patients. Meanwhile, studies also found that chronic obstructive pulmonary disease (COPD) was highly associated with lung cancer prognosis. In this study, we investigated and evaluated the correlations between COPD image features and ERCC1 gene expression. A database involving 106 NSCLC patients was used. Each patient had a thoracic CT examination and ERCC1 genetic test. We applied a computer-aided detection scheme to segment and quantify COPD image features. A logistic regression method and a multilayer perceptron network were applied to analyze the correlation between the computed COPD image features and ERCC1 protein expression. A multilayer perceptron network (MPN) was also developed to test performance of using COPD-related image features to predict ERCC1 protein expression. A nine feature based logistic regression analysis showed the average COPD feature values in the low and high ERCC1 protein expression groups are significantly different (p < 0.01). Using a five-fold cross validation method, the MPN yielded an area under ROC curve (AUC = 0.669±0.053) in classifying between the low and high ERCC1 expression cases. The study indicates that CT phenotype features are associated with the genetic tests, which may provide supplementary information to help improve accuracy in assessing prognosis of NSCLC patients.

Genetic factors contribute to bleeding after cardiac surgery.

PubMed

Welsby, I J; Podgoreanu, M V; Phillips-Bute, B; Mathew, J P; Smith, P K; Newman, M F; Schwinn, D A; Stafford-Smith, M

2005-06-01

Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter-patient variability poorly explained by clinical, procedural, and biological markers. We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two-way gene-gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T, GPIb alpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson's disease.

PubMed

Altmann, Vivian; Schumacher-Schuh, Artur F; Rieck, Mariana; Callegari-Jacques, Sidia M; Rieder, Carlos R M; Hutz, Mara H

2016-04-01

Levodopa is first-line treatment of Parkinson's disease motor symptoms but, dose response is highly variable. Therefore, the aim of this study was to determine how much levodopa dose could be explained by biological, pharmacological and genetic factors. A total of 224 Parkinson's disease patients were genotyped for SV2C and SLC6A3 polymorphisms by allelic discrimination assays. Comedication, demographic and clinical data were also assessed. All variables with p < 0.20 were included in a multiple regression analysis for dose prediction. The final model explained 23% of dose variation (F = 11.54; p < 0.000001). Although a good prediction model was obtained, it still needs to be tested in an independent sample to be validated.

Paleoclimatic modeling and phylogeography of least killifish, Heterandria formosa: insights into Pleistocene expansion-contraction dynamics and evolutionary history of North American Coastal Plain freshwater biota

PubMed Central

2013-01-01

Background Climatic and sea-level fluctuations throughout the last Pleistocene glacial cycle (~130-0 ka) profoundly influenced present-day distributions and genetic diversity of Northern Hemisphere biotas by forcing range contractions in many species during the glacial advance and allowing expansion following glacial retreat ('expansion-contraction’ model). Evidence for such range dynamics and refugia in the unglaciated Gulf-Atlantic Coastal Plain stems largely from terrestrial species, and aquatic species Pleistocene responses remain relatively uninvestigated. Heterandria formosa, a wide-ranging regional endemic, presents an ideal system to test the expansion-contraction model within this biota. By integrating ecological niche modeling and phylogeography, we infer the Pleistocene history of this livebearing fish (Poeciliidae) and test for several predicted distributional and genetic effects of the last glaciation. Results Paleoclimatic models predicted range contraction to a single southwest Florida peninsula refugium during the Last Glacial Maximum, followed by northward expansion. We inferred spatial-population subdivision into four groups that reflect genetic barriers outside this refuge. Several other features of the genetic data were consistent with predictions derived from an expansion-contraction model: limited intraspecific divergence (e.g. mean mtDNA p-distance = 0.66%); a pattern of mtDNA diversity (mean Hd = 0.934; mean π = 0.007) consistent with rapid, recent population expansion; a lack of mtDNA isolation-by-distance; and clinal variation in allozyme diversity with higher diversity at lower latitudes near the predicted refugium. Statistical tests of mismatch distributions and coalescent simulations of the gene tree lent greater support to a scenario of post-glacial expansion and diversification from a single refugium than to any other model examined (e.g. multiple-refugia scenarios). Conclusions Congruent results from diverse data indicate H. formosa fits the classic Pleistocene expansion-contraction model, even as the genetic data suggest additional ecological influences on population structure. While evidence for Plio-Pleistocene Gulf Coast vicariance is well described for many freshwater species presently codistributed with H. formosa, this species demography and diversification departs notably from this pattern. Species-specific expansion-contraction dynamics may therefore have figured more prominently in shaping Coastal Plain evolutionary history than previously thought. Our findings bolster growing appreciation for the complexity of phylogeographical structuring within North America’s southern refugia, including responses of Coastal Plain freshwater biota to Pleistocene climatic fluctuations. PMID:24107245

Filtering genetic variants and placing informative priors based on putative biological function.

PubMed

Friedrichs, Stefanie; Malzahn, Dörthe; Pugh, Elizabeth W; Almeida, Marcio; Liu, Xiao Qing; Bailey, Julia N

2016-02-03

High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.

Tolerance and potential for adaptation of a Baltic Sea rockweed under predicted climate change conditions.

PubMed

Rugiu, Luca; Manninen, Iita; Rothäusler, Eva; Jormalainen, Veijo

2018-03-01

Climate change is threating species' persistence worldwide. To predict species responses to climate change we need information not just on their environmental tolerance but also on its adaptive potential. We tested how the foundation species of rocky littoral habitats, Fucus vesiculosus, responds to combined hyposalinity and warming projected to the Baltic Sea by 2070-2099. We quantified responses of replicated populations originating from the entrance, central, and marginal Baltic regions. Using replicated individuals, we tested for the presence of within-population tolerance variation. Future conditions hampered growth and survival of the central and marginal populations whereas the entrance populations fared well. Further, both the among- and within-population variation in responses to climate change indicated existence of genetic variation in tolerance. Such standing genetic variation provides the raw material necessary for adaptation to a changing environment, which may eventually ensure the persistence of the species in the inner Baltic Sea. Copyright © 2017 Elsevier Ltd. All rights reserved.

Predictive genetic testing for adult-onset disorders in minors: a critical analysis of the arguments for and against the 2013 ACMG guidelines.

PubMed

Anderson, J A; Hayeems, R Z; Shuman, C; Szego, M J; Monfared, N; Bowdin, S; Zlotnik Shaul, R; Meyn, M S

2015-04-01

The publication of the ACMG recommendations has reignited the debate over predictive testing for adult-onset disorders in minors. Response has been polarized. With this in mind, we review and critically analyze this debate. First, we identify long-standing inconsistencies between consensus guidelines and clinical practice regarding risk assessment for adult-onset genetic disorders in children using family history and molecular analysis. Second, we discuss the disparate assumptions regarding the nature of whole genome and exome sequencing underlying arguments of both supporters and critics, and the role these assumptions play in the arguments for and against reporting. Third, we suggest that implicit differences regarding the definition of best interests of the child underlie disparate conclusions as to the best interests of children in this context. We conclude by calling for clarity and consensus concerning the central foci of this debate. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic evidence for polygynandry in the black-striped pipefish Syngnathus abaster: a microsatellite-based parentage analysis.

PubMed

Hübner, Kerstin; Gonzalez-Wanguemert, Mercedes; Diekmann, Onno E; Serrão, Ester A

2013-01-01

Sexual selection theory predicts that, in organisms with reversed sex roles, more polyandrous species exhibit higher levels of sexual dimorphism. In the family Syngnathidae (pipefish, seahorses, and seadragons), males provide all parental care by carrying developing embryos on their ventral surfaces, and females develop secondary sex characters. Syngnathids exhibit a variety of genetic mating patterns, making them an ideal group to test predictions of sexual selection theory. Here, we describe the mating system of the black-striped pipefish Syngnathus abaster, using 4 highly variable microsatellites to analyze parentage of 102 embryos. Results revealed that 1) both sexes mate multiple times over the course of a pregnancy (polygynandrous mating system), 2) eggs are spatially segregated by maternity within each brood pouch, and 3) larger females have higher mating success (Kolmogorov-Smirnov test; P < 0.05). Together with similar studies of other syngnathid species, our results support the hypothesis that the mating system is related to the intensity of sexual dimorphism.

BRCA1/2 Test Results Impact Risk Management Attitudes, Intentions and Uptake

PubMed Central

O’Neill, Suzanne C.; Valdimarsdottir, Heiddis B.; DeMarco, Tiffani A.; Peshkin, Beth N.; Graves, Kristi D.; Brown, Karen; Hurley, Karen E.; Isaacs, Claudine; Hecker, Sharon; Schwartz, Marc D.

2011-01-01

BACKGROUND Women who receive positive or uninformative BRCA1/2 test results face a number of decisions about how to manage their cancer risk. The purpose of this study was to prospectively examine the effect of receiving a positive vs. uninformative BRCA1/2 genetic test result on the perceived pros and cons of risk-reducing mastectomy (RRM) and risk-reducing oophorectomy (RRO) and breast cancer screening. We further examined how perceived pros and cons of surgery predict intention for and uptake of surgery. METHODS 308 women (146 positive, 162 uninformative) were included in RRM and breast cancer screening analyses. 276 women were included in RRO analyses. Participants completed questionnaires at pre-disclosure baseline and 1-, 6-and 12-months post-disclosure. We used linear multiple regression to assess whether test result contributed to change in pros and cons and logistic regression to predict intentions and surgery uptake. RESULTS Receipt of a positive BRCA1/2 test result predicted stronger pros for RRM and RRO (Ps < .001), but not perceived cons of RRM and RRO. Pros of surgery predicted RRM and RRO intentions in carriers and RRO intentions in uninformatives. Cons predicted RRM intentions in carriers. Pros and cons predicted carriers’ RRO uptake in the year after testing (Ps < .001). CONCLUSIONS Receipt of BRCA1/2 mutation test results impacts how carriers see the positive aspects of RRO and RRM and their surgical intentions. Both the positive and negative aspects predict uptake of surgery. PMID:20383578

A Genetically Optimized Predictive System for Success in General Chemistry Using a Diagnostic Algebra Test

NASA Astrophysics Data System (ADS)

Cooper, Cameron I.; Pearson, Paul T.

2012-02-01

In higher education, many high-enrollment introductory courses have evolved into "gatekeeper" courses due to their high failure rates. These courses prevent many students from attaining their educational goals and often become graduation roadblocks. At the authors' home institution, general chemistry has become a gatekeeper course in which approximately 25% of students do not pass. This failure rate in chemistry is common, and often higher, at many other institutions of higher education, and mathematical deficiencies are perceived to be a large contributing factor. This paper details the development of a highly accurate predictive system that identifies students at the beginning of the semester who are "at-risk" for earning a grade of C- or below in chemistry. The predictive accuracy of this system is maximized by using a genetically optimized neural network to analyze the results of a diagnostic algebra test designed for a specific population. Once at-risk students have been identified, they can be helped to improve their chances of success using techniques such as concurrent support courses, online tutorials, "just-in-time" instructional aides, study skills, motivational interviewing, and/or peer mentoring.

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations.

PubMed

Manchanda, Ranjit; Burnell, Matthew; Loggenberg, Kelly; Desai, Rakshit; Wardle, Jane; Sanderson, Saskia C; Gessler, Sue; Side, Lucy; Balogun, Nyala; Kumar, Ajith; Dorkins, Huw; Wallis, Yvonne; Chapman, Cyril; Tomlinson, Ian; Taylor, Rohan; Jacobs, Chris; Legood, Rosa; Raikou, Maria; McGuire, Alistair; Beller, Uziel; Menon, Usha; Jacobs, Ian

2016-07-01

Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches. 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=£7787 and TC=£17 307. DVD-C resulted in cost savings=£9520 (£14/volunteer). DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC. ISRCTN 73338115. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Unlocking Diversity in Germplasm Collections via Genomic Selection: A Case Study Based on Quantitative Adult Plant Resistance to Stripe Rust in Spring Wheat.

PubMed

Muleta, Kebede T; Bulli, Peter; Zhang, Zhiwu; Chen, Xianming; Pumphrey, Michael

2017-11-01

Harnessing diversity from germplasm collections is more feasible today because of the development of lower-cost and higher-throughput genotyping methods. However, the cost of phenotyping is still generally high, so efficient methods of sampling and exploiting useful diversity are needed. Genomic selection (GS) has the potential to enhance the use of desirable genetic variation in germplasm collections through predicting the genomic estimated breeding values (GEBVs) for all traits that have been measured. Here, we evaluated the effects of various scenarios of population genetic properties and marker density on the accuracy of GEBVs in the context of applying GS for wheat ( L.) germplasm use. Empirical data for adult plant resistance to stripe rust ( f. sp. ) collected on 1163 spring wheat accessions and genotypic data based on the wheat 9K single nucleotide polymorphism (SNP) iSelect assay were used for various genomic prediction tests. Unsurprisingly, the results of the cross-validation tests demonstrated that prediction accuracy increased with an increase in training population size and marker density. It was evident that using all the available markers (5619) was unnecessary for capturing the trait variation in the germplasm collection, with no further gain in prediction accuracy beyond 1 SNP per 3.2 cM (∼1850 markers), which is close to the linkage disequilibrium decay rate in this population. Collectively, our results suggest that larger germplasm collections may be efficiently sampled via lower-density genotyping methods, whereas genetic relationships between the training and validation populations remain critical when exploiting GS to select from germplasm collections. Copyright © 2017 Crop Science Society of America.

Testcross additive and dominance effects in best linear unbiased prediction of maize single-cross performance.

PubMed

Bernardo, R

1996-11-01

Best linear unbiased prediction (BLUP) has been found to be useful in maize (Zea mays L.) breeding. The advantage of including both testcross additive and dominance effects (Intralocus Model) in BLUP, rather than only testcross additive effects (Additive Model), has not been clearly demonstrated. The objective of this study was to compare the usefulness of Intralocus and Additive Models for BLUP of maize single-cross performance. Multilocation data from 1990 to 1995 were obtained from the hybrid testing program of Limagrain Genetics. Grain yield, moisture, stalk lodging, and root lodging of untested single crosses were predicted from (1) the performance of tested single crosses and (2) known genetic relationships among the parental inbreds. Correlations between predicted and observed performance were obtained with a delete-one cross-validation procedure. For the Intralocus Model, the correlations ranged from 0.50 to 0.66 for yield, 0.88 to 0.94 for moisture, 0.47 to 0.69 for stalk lodging, and 0.31 to 0.45 for root lodging. The BLUP procedure was consistently more effective with the Intralocus Model than with the Additive Model. When the Additive Model was used instead of the Intralocus Model, the reductions in the correlation were largest for root lodging (0.06-0.35), smallest for moisture (0.00-0.02), and intermediate for yield (0.02-0.06) and stalk lodging (0.02-0.08). The ratio of dominance variance (v D) to total genetic variance (v G) was highest for root lodging (0.47) and lowest for moisture (0.10). The Additive Model may be used if prior information indicates that VD for a given trait has little contribution to VG. Otherwise, the continued use of the Intralocus Model for BLUP of single-cross performance is recommended.

A Model of Compound Heterozygous, Loss-of-Function Alleles Is Broadly Consistent with Observations from Complex-Disease GWAS Datasets

PubMed Central

Sanjak, Jaleal S.; Long, Anthony D.; Thornton, Kevin R.

2017-01-01

The genetic component of complex disease risk in humans remains largely unexplained. A corollary is that the allelic spectrum of genetic variants contributing to complex disease risk is unknown. Theoretical models that relate population genetic processes to the maintenance of genetic variation for quantitative traits may suggest profitable avenues for future experimental design. Here we use forward simulation to model a genomic region evolving under a balance between recurrent deleterious mutation and Gaussian stabilizing selection. We consider multiple genetic and demographic models, and several different methods for identifying genomic regions harboring variants associated with complex disease risk. We demonstrate that the model of gene action, relating genotype to phenotype, has a qualitative effect on several relevant aspects of the population genetic architecture of a complex trait. In particular, the genetic model impacts genetic variance component partitioning across the allele frequency spectrum and the power of statistical tests. Models with partial recessivity closely match the minor allele frequency distribution of significant hits from empirical genome-wide association studies without requiring homozygous effect sizes to be small. We highlight a particular gene-based model of incomplete recessivity that is appealing from first principles. Under that model, deleterious mutations in a genomic region partially fail to complement one another. This model of gene-based recessivity predicts the empirically observed inconsistency between twin and SNP based estimated of dominance heritability. Furthermore, this model predicts considerable levels of unexplained variance associated with intralocus epistasis. Our results suggest a need for improved statistical tools for region based genetic association and heritability estimation. PMID:28103232

Key messages for communicating information about BRCA1 and BRCA2 to women with breast or ovarian cancer: Consensus across health professionals and service users.

PubMed

Jacobs, Chris; Pichert, Gabriella; Harris, Jackie; Tucker, Kathy; Michie, Susan

2017-11-01

Genetic testing of cancer predisposing genes will increasingly be needed in oncology clinics to target cancer treatment. This Delphi study aimed to identify areas of agreement and disagreement between genetics and oncology health professionals and service users about the key messages required by women with breast/ovarian cancer who undergo BRCA1/BRCA2 genetic testing and the optimal timing of communicating key messages. Participants were 16 expert health professionals specialising in oncology/genetics and 16 service users with breast/ovarian cancer and a pathogenic BRCA1/BRCA2 variant. Online questionnaires containing 53 inductively developed information messages were circulated to the groups separately. Participants rated each message as key/not key on a Likert scale and suggested additional messages. Questionnaires were modified according to the feedback and up to 3 rounds were circulated. Consensus was reached when there was ≥75% agreement. Thirty key messages were agreed by both groups with 7 of the key messages agreed by ≥95% of participants: dominant inheritance, the availability of predictive testing, the importance of pretest discussion, increased risk of breast and ovarian cancer, and the option of risk-reducing mastectomy and bilateral salpingo-oophorectomy. Both groups agreed that key messages should be communicated before genetic testing and once a pathogenic variant has been identified. There was a high level of agreement within and between the groups about the information requirements of women with breast/ovarian cancer about BRCA1/BRCA2. These key messages will be helpful in developing new approaches to the delivery of information as genetic testing becomes further integrated into mainstream oncology services. Copyright © 2017 John Wiley & Sons, Ltd.

Heritability and genetic correlations of personality traits in a wild population of yellow-bellied marmots (Marmota flaviventris).

PubMed

Petelle, M B; Martin, J G A; Blumstein, D T

2015-10-01

Describing and quantifying animal personality is now an integral part of behavioural studies because individually distinctive behaviours have ecological and evolutionary consequences. Yet, to fully understand how personality traits may respond to selection, one must understand the underlying heritability and genetic correlations between traits. Previous studies have reported a moderate degree of heritability of personality traits, but few of these studies have either been conducted in the wild or estimated the genetic correlations between personality traits. Estimating the additive genetic variance and covariance in the wild is crucial to understand the evolutionary potential of behavioural traits. Enhanced environmental variation could reduce heritability and genetic correlations, thus leading to different evolutionary predictions. We estimated the additive genetic variance and covariance of docility in the trap, sociability (mirror image stimulation), and exploration and activity in two different contexts (open-field and mirror image simulation experiments) in a wild population of yellow-bellied marmots (Marmota flaviventris). We estimated both heritability of behaviours and of personality traits and found nonzero additive genetic variance in these traits. We also found nonzero maternal, permanent environment and year effects. Finally, we found four phenotypic correlations between traits, and one positive genetic correlation between activity in the open-field test and sociability. We also found permanent environment correlations between activity in both tests and docility and exploration in the MIS test. This is one of a handful of studies to adopt a quantitative genetic approach to explain variation in personality traits in the wild and, thus, provides important insights into the potential variance available for selection. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis).

PubMed

Funk, W Chris; Lovich, Robert E; Hohenlohe, Paul A; Hofman, Courtney A; Morrison, Scott A; Sillett, T Scott; Ghalambor, Cameron K; Maldonado, Jesus E; Rick, Torben C; Day, Mitch D; Polato, Nicholas R; Fitzpatrick, Sarah W; Coonan, Timothy J; Crooks, Kevin R; Dillon, Adam; Garcelon, David K; King, Julie L; Boser, Christina L; Gould, Nicholas; Andelt, William F

2016-05-01

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of six subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1-89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland grey foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6-6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness and reduced adaptive potential. © 2016 John Wiley & Sons Ltd.

What do men understand about lifetime risk following genetic testing? The effect of context and numeracy.

PubMed

Rolison, Jonathan J; Hanoch, Yaniv; Miron-Shatz, Talya

2012-07-01

Genetic testing for gene mutations associated with specific cancers provides an opportunity for early detection, surveillance, and intervention (Smith, Cokkinides, & Brawley, 2008). Lifetime risk estimates provided by genetic testing refer to the risk of developing a specific disease within one's lifetime, and evidence suggests that this is important for the medical choices people make, as well as their future family and financial plans. The present studies tested whether adult men understand the lifetime risks of prostate cancer informed by genetic testing. In 2 experiments, adult men were asked to interpret the lifetime risk information provided in statements about risks of prostate cancer. Statement format was manipulated such that the most appropriate interpretation of risk statements referred to an absolute risk of cancer in experiment 1 and a relative risk in experiment 2. Experiment 1 revealed that few men correctly interpreted the lifetime risks of cancer when these refer to an absolute risk of cancer, and numeracy levels positively predicted correct responding. The proportion of correct responses was greatly improved in experiment 2 when the most appropriate interpretation of risk statements referred instead to a relative rather than an absolute risk, and numeracy levels were less involved. Understanding of lifetime risk information is often poor because individuals incorrectly believe that these refer to relative rather than absolute risks of cancer.

Feasibility of an Assessment Tool for Children's Competence to Consent to Predictive Genetic Testing: a Pilot Study.

PubMed

Hein, Irma M; Troost, Pieter W; Lindeboom, Robert; Christiaans, Imke; Grisso, Thomas; van Goudoever, Johannes B; Lindauer, Ramón J L

2015-12-01

Knowledge on children's capacities to consent to medical treatment is limited. Also, age limits for asking children's consent vary considerably between countries. Decision-making on predictive genetic testing (PGT) is especially complicated, considering the ongoing ethical debate. In order to examine just age limits for alleged competence to consent in children, we evaluated feasibility of a standardized assessment tool, and investigated cutoff ages for children's competence to consent to PGT. We performed a pilot study, including 17 pediatric outpatients between 6 and 18 years at risk for an autosomal dominantly inherited cardiac disease, eligible for predictive genetic testing. The reference standard for competence was established by experts trained in the relevant criteria for competent decision-making. The MacArthur Competence Assessment Tool for Treatment (MacCAT-T) served as index test. Data analysis included raw agreement between competence classifications, difference in mean ages between children judged competent and judged incompetent, and estimation of cutoff ages for judgments of competence. Twelve (71 %) children were considered competent by the reference standard, and 16 (94 %) by the MacCAT-T, with an overall agreement of 76 %. The expert judgments disagreed in most cases, while the MacCAT-T judgments agreed in 65 %. Mean age of children judged incompetent was 9.3 years and of children judged competent 12.1 years (p = .035). With 90 % sensitivity, children younger than 10.0 years were judged incompetent, with 90 % specificity children older than 11.8 years were judged competent. Feasibility of the MacCAT-T in children is confirmed. Initial findings on age cutoffs are indicative for children between the age of 12 and 18 to be judged competent for involvement in the informed consent process. Future research on appropriate age-limits for children's alleged competence to consent is needed.

Ethical and social implications of genetic testing for communication disorders.

PubMed

Arnos, Kathleen S

2008-01-01

Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in the identification of genes involved in the normal process of hearing. The resulting clinical applications have presented consumers with new information and choices. Many of the same gene identification techniques are increasingly being applied to the investigation of complex disorders of speech and language. In parallel with gene identification, studies of the legal, ethical and psychosocial impacts of the clinical application of these advances and their influence on specific behaviors of individuals with communication disorders are paramount, but often lag behind. These studies will help to ensure that new technologies are introduced into clinical practice in a responsible manner. As a result of this activity, the participant will be able to (1) explain the differences between Mendelian and complex forms of inheritance and why these differences complicate the ethical impact of genetic testing, (2) explain how publicly funded genome research through the Human Genome Project, the International HapMap Project and others have examined the ethical, legal and social implications of genome research, (3) list some of the ethical complexities of prenatal, newborn and predictive testing for various genetic disorders and (4) discuss the importance of evidence-based practice to the development of public policy for the introduction and clinical use of genetic tests.

Ethical and social implications of genetic testing for communication disorders

PubMed Central

Arnos, Kathleen S.

2013-01-01

Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in the identification of genes involved in the normal process of hearing. The resulting clinical applications have presented consumers with new information and choices. Many of the same gene identification techniques are increasingly being applied to the investigation of complex disorders of speech and language. In parallel with gene identification, studies of the legal, ethical and psychosocial impacts of the clinical application of these advances and their influence on specific behaviors of individuals with communication disorders are paramount, but often lag behind. These studies will help to ensure that new technologies are introduced into clinical practice in a responsible manner. Learning outcomes As a result of this activity, the participant will be able to (1) explain the differences between Mendelian and complex forms of inheritance and why these differences complicate the ethical impact of genetic testing, (2) explain how publicly funded genome research through the Human Genome Project, the International HapMap Project and others have examined the ethical, legal and social implications of genome research, (3) list some of the ethical complexities of prenatal, newborn and predictive testing for various genetic disorders and (4) discuss the importance of evidence-based practice to the development of public policy for the introduction and clinical use of genetic tests. PMID:18452941

Prevalence and healthcare actions of women in a large health system with a family history meeting the 2005 USPSTF recommendation for BRCA genetic counseling referral.

PubMed

Bellcross, Cecelia A; Leadbetter, Steven; Alford, Sharon Hensley; Peipins, Lucy A

2013-04-01

In 2005, the United States Preventive Services Task Force (USPSTF) released guidelines which outlined specific family history patterns associated with an increased risk for BRCA1/2 mutations, and recommended at-risk individuals be referred for genetic counseling and evaluation for BRCA testing. The purpose of this study was to assess the prevalence of individuals with a USPSTF increased-risk family history pattern, the frequency with which specific patterns were met, and resulting healthcare actions among women from the Henry Ford Health System. As part of a study evaluating ovarian cancer risk perception and screening, 2,524 randomly selected participants completed a detailed interview (response rate 76%) from an initial eligible cohort of 16,720 women. Approximately 6% of participants had a family history fulfilling one or more of the USPSTF patterns. Although 90% of these women had shared their family history with their provider, less than 20% had been referred for genetic counseling and only 8% had undergone genetic testing. Caucasian women with higher income and education levels were more likely to receive referrals. Among the 95 participants in the total study cohort who reported BRCA testing, 78% did not have a family history that met one of the USPSTF patterns. These results suggest a higher prevalence of women with an increased-risk family history than originally predicted by the USPSTF, and lack of provider recognition and referral for genetic services. Improvements in healthcare infrastructure and clinician education will be required to realize population level benefits from BRCA genetic counseling and testing.

Pharmacogenetics and Predictive Testing of Drug Hypersensitivity Reactions.

PubMed

Böhm, Ruwen; Cascorbi, Ingolf

2016-01-01

Adverse drug reactions adverse drug reaction (ADR) occur in approximately 17% of patients. Avoiding ADR is thus mandatory from both an ethical and an economic point of view. Whereas, pharmacogenetics changes of the pharmacokinetics may contribute to the explanation of some type A reactions, strong relationships of genetic markers has also been shown for drug hypersensitivity belonging to type B reactions. We present the classifications of ADR, discuss genetic influences and focus on delayed-onset hypersensitivity reactions, i.e., drug-induced liver injury, drug-induced agranulocytosis, and severe cutaneous ADR. A guidance how to read and interpret the contingency table is provided as well as an algorithm whether and how a test for a pharmacogenetic biomarker should be conducted.

Genetic risk prediction and neurobiological understanding of alcoholism

PubMed Central

Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; Kiefe, F; Wodarz, N; Müller-Myhsok, B; Dahmen, N; Nöthen, M; Sherva, R; Farrer, L; Smith, A H; Kranzler, H R; Rietschel, M; Gelernter, J; Niculescu, A B

2014-01-01

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape. PMID:24844177

On the suitability of different representations of solid catalysts for combinatorial library design by genetic algorithms.

PubMed

Gobin, Oliver C; Schüth, Ferdi

2008-01-01

Genetic algorithms are widely used to solve and optimize combinatorial problems and are more often applied for library design in combinatorial chemistry. Because of their flexibility, however, their implementation can be challenging. In this study, the influence of the representation of solid catalysts on the performance of genetic algorithms was systematically investigated on the basis of a new, constrained, multiobjective, combinatorial test problem with properties common to problems in combinatorial materials science. Constraints were satisfied by penalty functions, repair algorithms, or special representations. The tests were performed using three state-of-the-art evolutionary multiobjective algorithms by performing 100 optimization runs for each algorithm and test case. Experimental data obtained during the optimization of a noble metal-free solid catalyst system active in the selective catalytic reduction of nitric oxide with propene was used to build up a predictive model to validate the results of the theoretical test problem. A significant influence of the representation on the optimization performance was observed. Binary encodings were found to be the preferred encoding in most of the cases, and depending on the experimental test unit, repair algorithms or penalty functions performed best.

Scientific reporting is suboptimal for aspects that characterize genetic risk prediction studies: a review of published articles based on the Genetic RIsk Prediction Studies statement.

PubMed

Iglesias, Adriana I; Mihaescu, Raluca; Ioannidis, John P A; Khoury, Muin J; Little, Julian; van Duijn, Cornelia M; Janssens, A Cecile J W

2014-05-01

Our main objective was to raise awareness of the areas that need improvements in the reporting of genetic risk prediction articles for future publications, based on the Genetic RIsk Prediction Studies (GRIPS) statement. We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted. Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as genetic risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the risk model. Completeness of reporting in genetic risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize genetic risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of genetic risk prediction models. Copyright © 2014 Elsevier Inc. All rights reserved.

Empathy in early childhood: genetic, environmental, and affective contributions.

PubMed

Knafo, Ariel; Zahn-Waxler, Carolyn; Davidov, Maayan; Van Hulle, Carol; Robinson, JoAnn L; Rhee, Soo Hyun

2009-06-01

We investigated the genetic and environmental origins of children's empathy toward a distress victim and its correlates with emotional symptoms and affective knowledge. The cognitive (hypothesis testing) and affective (empathic concern) empathy of 122 twin pairs in response to simulated pain by an adult examiner was observed at 3.5 years of age. Moderate (0.19 to 0.44) heritabilities were estimated for individual differences in empathy, and the nonshared environment and error accounted for the rest of the variance. Hypothesis testing and empathic concern were moderately correlated, mainly through overlapping genetic effects. Although children's affective knowledge did not correlate with their empathy, affective knowledge interacted with mother-rated emotional symptoms in predicting empathy; knowledge about emotions was associated with greater empathy in children low in emotional symptoms. In contrast, among children with high degrees of emotional symptoms, those with better affective knowledge tended to show lower empathy.

Wear rate optimization of Al/SiCnp/e-glass fibre hybrid metal matrix composites using Taguchi method and genetic algorithm and development of wear model using artificial neural networks

NASA Astrophysics Data System (ADS)

Bongale, Arunkumar M.; Kumar, Satish; Sachit, T. S.; Jadhav, Priya

2018-03-01

Studies on wear properties of Aluminium based hybrid nano composite materials, processed through powder metallurgy technique, are reported in the present study. Silicon Carbide nano particles and E-glass fibre are reinforced in pure aluminium matrix to fabricate hybrid nano composite material samples. Pin-on-Disc wear testing equipment is used to evaluate dry sliding wear properties of the composite samples. The tests were conducted following the Taguchi’s Design of Experiments method. Signal-to-Noise ratio analysis and Analysis of Variance are carried out on the test data to find out the influence of test parameters on the wear rate. Scanning Electron Microscopic analysis and Energy Dispersive x-ray analysis are conducted on the worn surfaces to find out the wear mechanisms responsible for wear of the composites. Multiple linear regression analysis and Genetic Algorithm techniques are employed for optimization of wear test parameters to yield minimum wear of the composite samples. Finally, a wear model is built by the application of Artificial Neural Networks to predict the wear rate of the composite material, under different testing conditions. The predicted values of wear rate are found to be very close to the experimental values with a deviation in the range of 0.15% to 8.09%.

The evolution of sexes: A specific test of the disruptive selection theory.

PubMed

da Silva, Jack

2018-01-01

The disruptive selection theory of the evolution of anisogamy posits that the evolution of a larger body or greater organismal complexity selects for a larger zygote, which in turn selects for larger gametes. This may provide the opportunity for one mating type to produce more numerous, small gametes, forcing the other mating type to produce fewer, large gametes. Predictions common to this and related theories have been partially upheld. Here, a prediction specific to the disruptive selection theory is derived from a previously published game-theoretic model that represents the most complete description of the theory. The prediction, that the ratio of macrogamete to microgamete size should be above three for anisogamous species, is supported for the volvocine algae. A fully population genetic implementation of the model, involving mutation, genetic drift, and selection, is used to verify the game-theoretic approach and accurately simulates the evolution of gamete sizes in anisogamous species. This model was extended to include a locus for gamete motility and shows that oogamy should evolve whenever there is costly motility. The classic twofold cost of sex may be derived from the fitness functions of these models, showing that this cost is ultimately due to genetic conflict.

The evolution of trade-offs: testing predictions on response to selection and environmental variation.

PubMed

Roff, Derek A; Mostowy, Serge; Fairbairn, Daphne J

2002-01-01

The concept of phenotypic trade-offs is a central element in evolutionary theory. In general, phenotypic models assume a fixed trade-off function, whereas quantitative genetic theory predicts that the trade-off function will change as a result of selection. For a linear trade-off function selection will readily change the intercept but will have to be relatively stronger to change the slope. We test these predictions by examining the trade-off between fecundity and flight capability, as measured by dorso-longitudinal muscle mass, in four different populations of the sand cricket, Gryllus firmus. Three populations were recently derived from the wild, and the fourth had been in the laboratory for 19 years. We hypothesized that the laboratory population had most likely undergone more and different selection from the three wild populations and therefore should differ from these in respect to both slope and intercept. Because of geographic variation in selection, we predicted a general difference in intercept among the four populations. We further tested the hypothesis that this intercept will be correlated with proportion macropterous and that this relationship will itself vary with environmental conditions experienced during both the nymphal and adult period. Observed variation in the phenotypic trade-off was consistent with the predictions of the quantitative genetic model. These results point to the importance of modeling trade-offs as dynamic rather than static relationships. We discuss how phenotypic models can incorporate such variation. The phenotypic trade-off between fecundity and dorso-longitudinal muscle mass is determined in part by variation in body size, illustrating the necessity of considering trade-offs to be multi factorial rather than simply bivariate relationships.

Geographical gradients in selection can reveal genetic constraints for evolutionary responses to ocean acidification

PubMed Central

Gaitán-Espitia, Juan Diego; Marshall, Dustin; Dupont, Sam; Bacigalupe, Leonardo D.; Bodrossy, Levente; Hobday, Alistair J.

2017-01-01

Geographical gradients in selection can shape different genetic architectures in natural populations, reflecting potential genetic constraints for adaptive evolution under climate change. Investigation of natural pH/pCO2 variation in upwelling regions reveals different spatio-temporal patterns of natural selection, generating genetic and phenotypic clines in populations, and potentially leading to local adaptation, relevant to understanding effects of ocean acidification (OA). Strong directional selection, associated with intense and continuous upwellings, may have depleted genetic variation in populations within these upwelling regions, favouring increased tolerances to low pH but with an associated cost in other traits. In contrast, diversifying or weak directional selection in populations with seasonal upwellings or outside major upwelling regions may have resulted in higher genetic variances and the lack of genetic correlations among traits. Testing this hypothesis in geographical regions with similar environmental conditions to those predicted under climate change will build insights into how selection may act in the future and how populations may respond to stressors such as OA. PMID:28148831

Development and validation of a brief screening instrument for psychosocial risk associated with genetic testing: a pan-Canadian cohort study

PubMed Central

Esplen, Mary Jane; Cappelli, Mario; Wong, Jiahui; Bottorff, Joan L; Hunter, Jon; Carroll, June; Dorval, Michel; Wilson, Brenda; Allanson, Judith; Semotiuk, Kara; Aronson, Melyssa; Bordeleau, Louise; Charlemagne, Nicole; Meschino, Wendy

2013-01-01

Objectives To develop a brief, reliable and valid instrument to screen psychosocial risk among those who are undergoing genetic testing for Adult-Onset Hereditary Disease (AOHD). Design A prospective two-phase cohort study. Setting 5 genetic testing centres for AOHD, such as cancer, Huntington's disease or haemochromatosis, in ambulatory clinics of tertiary hospitals across Canada. Participants 141 individuals undergoing genetic testing were approached and consented to the instrument development phase of the study (Phase I). The Genetic Psychosocial Risk Instrument (GPRI) developed in Phase I was tested in Phase II for item refinement and validation. A separate cohort of 722 individuals consented to the study, 712 completed the baseline package and 463 completed all follow-up assessments. Most participants were female, at the mid-life stage. Individuals in advanced stages of the illness or with cognitive impairment or a language barrier were excluded. Interventions Phase I: GPRI items were generated from (1) a review of the literature, (2) input from genetic counsellors and (3) phase I participants. Phase II: further item refinement and validation were conducted with a second cohort of participants who completed the GPRI at baseline and were followed for psychological distress 1-month postgenetic testing results. Primary and secondary outcome measures GPRI, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Brief Symptom Inventory (BSI) and Impact of Event Scale (IES). Results The final 20-item GPRI had a high reliability—Cronbach's α at 0.81. The construct validity was supported by high correlations between GPRI and BSI and IES. The predictive value was demonstrated by a receiver operating characteristic curve of 0.78 plotting GPRI against follow-up assessments using HAM-D and HAM-A. Conclusions With a cut-off score of 50, GPRI identified 84% of participants who displayed distress postgenetic testing results, supporting its potential usefulness in a clinical setting. PMID:23485718

Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.

PubMed

Shapiro, Lucy; Chatterjee, Sumana; Ramadan, Dina G; Davies, Kate M; Savage, Martin O; Metherell, Louise A; Storr, Helen L

2017-12-01

GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres. © 2017 European Society of Endocrinology.

Development and Evolution of Character Displacement

PubMed Central

Pfennig, David W.; Pfennig, Karin S.

2012-01-01

Character displacement occurs when competition for either resources or successful reproduction imposes divergent selection on interacting species, causing divergence in traits associated with resource use or reproduction. Here, we describe how character displacement can be mediated either by genetically canalized changes (i.e., changes that reflect allelic or genotype frequency changes) or by phenotypic plasticity. We also discuss how these two mechanisms influence the tempo of character displacement. Specifically, we suggest that, under some conditions, character displacement mediated by phenotypic plasticity might occur more rapidly than that mediated by genetically canalized changes. Finally, we describe how these two mechanisms may act together and determine character displacement’s mode, such that it proceeds through an initial phase in which trait divergence is environmentally induced to a later phase in which divergence becomes genetically canalized. This plasticity-first hypothesis predicts that character displacement should be generally mediated by ancestral plasticity and that it will arise similarly in multiple, independently evolving populations. We conclude by highlighting future directions for research that would test these predictions. PMID:22257002

Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer.

PubMed

Witkiewicz, Agnieszka K; Balaji, Uthra; Eslinger, Cody; McMillan, Elizabeth; Conway, William; Posner, Bruce; Mills, Gordon B; O'Reilly, Eileen M; Knudsen, Erik S

2016-08-16

Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

PubMed

Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

2015-12-01

The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Integrating Genetic, Neuropsychological and Neuroimaging Data to Model Early-Onset Obsessive Compulsive Disorder Severity

PubMed Central

Mas, Sergi; Gassó, Patricia; Morer, Astrid; Calvo, Anna; Bargalló, Nuria; Lafuente, Amalia; Lázaro, Luisa

2016-01-01

We propose an integrative approach that combines structural magnetic resonance imaging data (MRI), diffusion tensor imaging data (DTI), neuropsychological data, and genetic data to predict early-onset obsessive compulsive disorder (OCD) severity. From a cohort of 87 patients, 56 with complete information were used in the present analysis. First, we performed a multivariate genetic association analysis of OCD severity with 266 genetic polymorphisms. This association analysis was used to select and prioritize the SNPs that would be included in the model. Second, we split the sample into a training set (N = 38) and a validation set (N = 18). Third, entropy-based measures of information gain were used for feature selection with the training subset. Fourth, the selected features were fed into two supervised methods of class prediction based on machine learning, using the leave-one-out procedure with the training set. Finally, the resulting model was validated with the validation set. Nine variables were used for the creation of the OCD severity predictor, including six genetic polymorphisms and three variables from the neuropsychological data. The developed model classified child and adolescent patients with OCD by disease severity with an accuracy of 0.90 in the testing set and 0.70 in the validation sample. Above its clinical applicability, the combination of particular neuropsychological, neuroimaging, and genetic characteristics could enhance our understanding of the neurobiological basis of the disorder. PMID:27093171

Pathway-Based Kernel Boosting for the Analysis of Genome-Wide Association Studies

PubMed Central

Manitz, Juliane; Burger, Patricia; Amos, Christopher I.; Chang-Claude, Jenny; Wichmann, Heinz-Erich; Kneib, Thomas; Bickeböller, Heike

2017-01-01

The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility. PMID:28785300

Pathway-Based Kernel Boosting for the Analysis of Genome-Wide Association Studies.

PubMed

Friedrichs, Stefanie; Manitz, Juliane; Burger, Patricia; Amos, Christopher I; Risch, Angela; Chang-Claude, Jenny; Wichmann, Heinz-Erich; Kneib, Thomas; Bickeböller, Heike; Hofner, Benjamin

2017-01-01

The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility.

Developing a clinical utility framework to evaluate prediction models in radiogenomics

NASA Astrophysics Data System (ADS)

Wu, Yirong; Liu, Jie; Munoz del Rio, Alejandro; Page, David C.; Alagoz, Oguzhan; Peissig, Peggy; Onitilo, Adedayo A.; Burnside, Elizabeth S.

2015-03-01

Combining imaging and genetic information to predict disease presence and behavior is being codified into an emerging discipline called "radiogenomics." Optimal evaluation methodologies for radiogenomics techniques have not been established. We aim to develop a clinical decision framework based on utility analysis to assess prediction models for breast cancer. Our data comes from a retrospective case-control study, collecting Gail model risk factors, genetic variants (single nucleotide polymorphisms-SNPs), and mammographic features in Breast Imaging Reporting and Data System (BI-RADS) lexicon. We first constructed three logistic regression models built on different sets of predictive features: (1) Gail, (2) Gail+SNP, and (3) Gail+SNP+BI-RADS. Then, we generated ROC curves for three models. After we assigned utility values for each category of findings (true negative, false positive, false negative and true positive), we pursued optimal operating points on ROC curves to achieve maximum expected utility (MEU) of breast cancer diagnosis. We used McNemar's test to compare the predictive performance of the three models. We found that SNPs and BI-RADS features augmented the baseline Gail model in terms of the area under ROC curve (AUC) and MEU. SNPs improved sensitivity of the Gail model (0.276 vs. 0.147) and reduced specificity (0.855 vs. 0.912). When additional mammographic features were added, sensitivity increased to 0.457 and specificity to 0.872. SNPs and mammographic features played a significant role in breast cancer risk estimation (p-value < 0.001). Our decision framework comprising utility analysis and McNemar's test provides a novel framework to evaluate prediction models in the realm of radiogenomics.

Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia*

PubMed Central

Silvent, Jérémie; Gasse, Barbara; Mornet, Etienne; Sire, Jean-Yves

2014-01-01

ALPL encodes the tissue nonspecific alkaline phosphatase (TNSALP), which removes phosphate groups from various substrates. Its function is essential for bone and tooth mineralization. In humans, ALPL mutations lead to hypophosphatasia, a genetic disorder characterized by defective bone and/or tooth mineralization. To date, 275 ALPL mutations have been reported to cause hypophosphatasia, of which 204 were simple missense mutations. Molecular evolutionary analysis has proved to be an efficient method to highlight residues important for the protein function and to predict or validate sensitive positions for genetic disease. Here we analyzed 58 mammalian TNSALP to identify amino acids unchanged, or only substituted by residues sharing similar properties, through 220 millions years of mammalian evolution. We found 469 sensitive positions of the 524 residues of human TNSALP, which indicates a highly constrained protein. Any substitution occurring at one of these positions is predicted to lead to hypophosphatasia. We tested the 204 missense mutations resulting in hypophosphatasia against our predictive chart, and validated 99% of them. Most sensitive positions were located in functionally important regions of TNSALP (active site, homodimeric interface, crown domain, calcium site, …). However, some important positions are located in regions, the structure and/or biological function of which are still unknown. Our chart of sensitive positions in human TNSALP (i) enables to validate or invalidate at low cost any ALPL mutation, which would be suspected to be responsible for hypophosphatasia, by contrast with time consuming and expensive functional tests, and (ii) displays higher predictive power than in silico models of prediction. PMID:25023282

Duchenne Muscular Dystrophy: a Survey of Perspectives on Carrier Testing and Communication Within the Family.

PubMed

Hayes, Brenna; Hassed, Susan; Chaloner, Jae Lindsay; Aston, Christopher E; Guy, Carrie

2016-06-01

Carrier testing is widely available for multiple genetic conditions, and several professional organizations have created practice guidelines regarding appropriate clinical application and the testing of minors. Previous research has focused on carrier screening, predictive testing, and testing for X-linked conditions. However, family perspectives on carrier testing for X-linked lethal diseases have yet to be described. In this study, we explored communication within the family about carrier testing and the perspectives of mothers of sons with an X-linked lethal disease, Duchenne muscular dystrophy (DMD). Twenty-five mothers of sons with DMD participated in an anonymous online survey. Survey questions included multiple choice, Likert scale, and open ended, short answer questions. Analysis of the multiple choice and Likert scale questions revealed that most mothers preferred a gradual style of communication with their daughters regarding risk status. In addition, most participants reported having consulted with a genetic counselor and found it helpful. Comparisons between groups, analyzed using Fisher's exact tests, found no differences in preferred style due to mother's carrier status or having a daughter. Thematic analysis was conducted on responses to open ended questions. Themes identified included the impact of family implications, age and maturity, and a desire for autonomy regarding the decision to discuss and undergo carrier testing with at-risk daughters, particularly timing of these discussions. Implications for genetic counseling practice are discussed.

Diagnosing ARVC in Pediatric Patients Applying the Revised Task Force Criteria: Importance of Imaging, 12-Lead ECG, and Genetics.

PubMed

Steinmetz, Michael; Krause, Ulrich; Lauerer, Peter; Konietschke, Frank; Aguayo, Randolph; Ritter, Christian Oliver; Schuster, Andreas; Lotz, Joachim; Paul, Thomas; Staab, Wieland

2018-05-12

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially lethal disease that is well described in adults. In pediatric patients, however, identification of patients at risk of adverse events of ARVC remains a challenge. We aimed to determine which criteria of the revised Task Force Criteria (rTFC), alone or combined, have an impact on diagnosis of ARVC when compared to disease-specific genetic mutations in pediatric patients ≤ 18 years. Between September 2010 and December 2013, 48 consecutive young patients ≤ 18 years of age (mean 14, range of 12.9-15.1 years) underwent contrast-enhanced magnetic resonance imaging (CMR), genetic testing, and comprehensive clinical work-up for ARVC criteria to test for clinically suspected ARVC. As specified by the rTFC, patients were grouped into four categories: "definite," "borderline," "possible," and "none" ARVC. Of the 48 patients, 12 were found to have gene mutations of either the desmoplakin (9/12) or plakophilin (3/12) locus. According to rTFC 12/48 patients were considered as "definite" ARVC (25%), while 10/12 (83.3%) had an ARVC-specific gene mutation. Of the remaining 36 patients, 6 (12.5%) were grouped as "borderline" ARVC, 7 (14.6%) as "possible" ARVC (including the remaining two genetic mutations), and 22 (45.8%) as "none" ARVC, respectively. Statistical analysis of ARVC criteria in patients diagnosed with "definite" ARVC revealed high prevalence of positive findings by imaging (CMR and echocardiography) and positive genetics. The positive predictive value to detect "definite" ARVC by genotyping was 83.3%, while the negative predictive value was 94%. Logistic regression analyses for different criteria combinations revealed that imaging modalities (echo and CMR combined) and abnormalities of 12-lead ECG were significant markers (p < 0.01). Positive results of endomyocardial biopsies or arrhythmia on ECG or Holter as defined by the rTFC were not significant in this analysis. The rTFC for ARVC should be used with caution in children and adolescents suspected for ARVC. 12-Lead ECG and imaging modalities (CMR and echo) were of major value, positive results should prompt genetic testing.

HIV-1 protease cleavage site prediction based on two-stage feature selection method.

PubMed

Niu, Bing; Yuan, Xiao-Cheng; Roeper, Preston; Su, Qiang; Peng, Chun-Rong; Yin, Jing-Yuan; Ding, Juan; Li, HaiPeng; Lu, Wen-Cong

2013-03-01

Knowledge of the mechanism of HIV protease cleavage specificity is critical to the design of specific and effective HIV inhibitors. Searching for an accurate, robust, and rapid method to correctly predict the cleavage sites in proteins is crucial when searching for possible HIV inhibitors. In this article, HIV-1 protease specificity was studied using the correlation-based feature subset (CfsSubset) selection method combined with Genetic Algorithms method. Thirty important biochemical features were found based on a jackknife test from the original data set containing 4,248 features. By using the AdaBoost method with the thirty selected features the prediction model yields an accuracy of 96.7% for the jackknife test and 92.1% for an independent set test, with increased accuracy over the original dataset by 6.7% and 77.4%, respectively. Our feature selection scheme could be a useful technique for finding effective competitive inhibitors of HIV protease.

Context-dependent sex allocation: constraints on the expression and evolution of maternal effects.

PubMed

Pryke, Sarah R; Rollins, Lee A; Griffith, Simon C

2011-10-01

Despite decades of research, whether vertebrates can and do adaptively adjust the sex ratio of their offspring is still highly debated. However, this may have resulted from the failure of empirical tests to identify large and predictable fitness returns to females from strategic adjustment. Here, we test the effect of diet quality and maternal condition on facultative sex ratio adjustment in the color polymorphic Gouldian finch (Erythrura gouldiae), a species that exhibits extreme maternal allocation in response to severe and predictable (genetically-determined) fitness costs. On high-quality diets, females produced a relatively equal sex ratio, but over-produced sons in poor dietary conditions. Despite the lack of sexual size dimorphism, nutritionally stressed foster sons were healthier, grew faster, and were more likely to survive than daughters. Although these findings are in line with predictions from sex allocation theory, the extent of adjustment is considerably lower than previously reported for this species. Females therefore have strong facultative control over sex allocation, but the extent of adjustment is likely determined by the relative magnitude of fitness gains and the ability to reliably predict sex-specific benefits from environmental (vs. genetic) variables. These findings may help explain the often inconsistent, weak, or inconclusive empirical evidence for adaptive sex ratio adjustment in vertebrates. © 2011 The Author(s). Evolution© 2011 The Society for the Study of Evolution.

Genetic and economic benefits of selection based on performance recording and genotyping in lower tiers of multi-tiered sheep breeding schemes.

PubMed

Santos, Bruno F S; van der Werf, Julius H J; Gibson, John P; Byrne, Timothy J; Amer, Peter R

2017-01-17

Performance recording and genotyping in the multiplier tier of multi-tiered sheep breeding schemes could potentially reduce the difference in the average genetic merit between nucleus and commercial flocks, and create additional economic benefits for the breeding structure. The genetic change in a multiple-trait breeding objective was predicted for various selection strategies that included performance recording, parentage testing and genomic selection. A deterministic simulation model was used to predict selection differentials and the flow of genetic superiority through the different tiers. Cumulative discounted economic benefits were calculated based on trait gains achieved in each of the tiers and considering the extra revenue and associated costs of applying recording, genotyping and selection practices in the multiplier tier of the breeding scheme. Performance recording combined with genomic or parentage information in the multiplier tier reduced the genetic lag between the nucleus and commercial flock by 2 to 3 years. The overall economic benefits of improved performance in the commercial tier offset the costs of recording the multiplier. However, it took more than 18 years before the cumulative net present value of benefits offset the costs at current test prices. Strategies in which recorded multiplier ewes were selected as replacements for the nucleus flock did modestly increase profitability when compared to a closed nucleus structure. Applying genomic selection is the most beneficial strategy if testing costs can be reduced or by genotyping only a proportion of the selection candidates. When the cost of genotyping was reduced, scenarios that combine performance recording with genomic selection were more profitable and reached breakeven point about 10 years earlier. Economic benefits can be generated in multiplier flocks by implementing performance recording in conjunction with either DNA pedigree recording or genomic technology. These recording practices reduce the long genetic lag between the nucleus and commercial flocks in multi-tiered breeding programs. Under current genotyping costs, the time to breakeven was found to be generally very long, although this varied between strategies. Strategies using either genomic selection or DNA pedigree verification were found to be economically viable provided the price paid for the tests is lower than current prices, in the long-term.

Genetic analysis for mastitis resistance and milk somatic cell score in French Lacaune dairy sheep

PubMed Central

Barillet, Francis; Rupp, Rachel; Mignon-Grasteau, Sandrine; Astruc, Jean-Michel; Jacquin, Michèle

2001-01-01

Genetic analysis for mastitis resistance was studied from two data sets. Firstly, risk factors for different mastitis traits, i.e. culling due to clinical or chronic mastitis and subclinical mastitis predicted from somatic cell count (SCC), were explored using data from 957 first lactation Lacaune ewes of an experimental INRA flock composed of two divergent lines for milk yield. Secondly, genetic parameters for SCC were estimated from 5 272 first lactation Lacaune ewes recorded among 38 flocks, using an animal model. In the experimental flock, the frequency of culling due to clinical mastitis (5%) was lower than that of subclinical mastitis (10%) predicted from SCC. Predicted subclinical mastitis was unfavourably associated with the milk yield level. Such an antagonism was not detected for clinical mastitis, which could result, to some extent, from its low frequency or from the limited amount of data. In practice, however, selection for mastitis resistance could be limited in a first approach to selection against subclinical mastitis using SCC. The heritability estimate of SCC was 0.15 for the lactation mean trait and varied from 0.04 to 0.12 from the first to the fifth test-day. The genetic correlation between lactation SCC and milk yield was slightly positive (0.15) but showed a strong evolution during lactation, i.e. from favourable (-0.48) to antagonistic (0.27). On a lactation basis, our results suggest that selection for mastitis resistance based on SCC is feasible. Patterns for genetic parameters within first lactation, however, require further confirmation and investigation. PMID:11559483

Predictive genomics DNA profiling for athletic performance.

PubMed

Kambouris, Marios; Ntalouka, Foteini; Ziogas, Georgios; Maffulli, Nicola

2012-12-01

Genes control biological processes such as muscle, cartilage and bone formation, muscle energy production and metabolism (mitochondriogenesis, lactic acid removal), blood and tissue oxygenation (erythropoiesis, angiogenesis, vasodilatation), all essential in sport and athletic performance. DNA sequence variations in such genes confer genetic advantages that can be exploited, or genetic 'barriers' that could be overcome to achieve optimal athletic performance. Predictive Genomic DNA Profiling for athletic performance reveals genetic variations that may be associated with better suitability for endurance, strength and speed sports, vulnerability to sports-related injuries and individualized nutritional requirements. Knowledge of genetic 'suitability' in respect to endurance capacity or strength and speed would lead to appropriate sport and athletic activity selection. Knowledge of genetic advantages and barriers would 'direct' an individualized training program, nutritional plan and nutritional supplementation to achieving optimal performance, overcoming 'barriers' that results from intense exercise and pressure under competition with minimum waste of time and energy and avoidance of health risks (hypertension, cardiovascular disease, inflammation, and musculoskeletal injuries) related to exercise, training and competition. Predictive Genomics DNA profiling for Athletics and Sports performance is developing into a tool for athletic activity and sport selection and for the formulation of individualized and personalized training and nutritional programs to optimize health and performance for the athlete. Human DNA sequences are patentable in some countries, while in others DNA testing methodologies [unless proprietary], are non patentable. On the other hand, gene and variant selection, genotype interpretation and the risk and suitability assigning algorithms based on the specific Genomic variants used are amenable to patent protection.

Strong spatial genetic structure in five tropical Piper species: should the Baker–Fedorov hypothesis be revived for tropical shrubs?

PubMed Central

Lasso, E; Dalling, J W; Bermingham, E

2011-01-01

Fifty years ago, Baker and Fedorov proposed that the high species diversity of tropical forests could arise from the combined effects of inbreeding and genetic drift leading to population differentiation and eventually to sympatric speciation. Decades of research, however have failed to support the Baker–Fedorov hypothesis (BFH), and it has now been discarded in favor of a paradigm where most trees are self-incompatible or strongly outcrossing, and where long-distance pollen dispersal prevents population drift. Here, we propose that several hyper-diverse genera of tropical herbs and shrubs, including Piper (>1,000 species), may provide an exception. Species in this genus often have aggregated, high-density populations with self-compatible breeding systems; characteristics which the BFH would predict lead to high local genetic differentiation. We test this prediction for five Piper species on Barro Colorado Island, Panama, using Amplified Fragment Length Polymorphism (AFLP) markers. All species showed strong genetic structure at both fine- and large-spatial scales. Over short distances (200–750 m) populations showed significant genetic differentiation (Fst 0.11–0.46, P < 0.05), with values of spatial genetic structure that exceed those reported for other tropical tree species (Sp = 0.03–0.136). This genetic structure probably results from the combined effects of limited seed and pollen dispersal, clonal spread, and selfing. These processes are likely to have facilitated the diversification of populations in response to local natural selection or genetic drift and may explain the remarkable diversity of this rich genus. PMID:22393518

Genetic and environmental influences on conduct and antisocial personality problems in childhood, adolescence, and adulthood.

PubMed

Wesseldijk, Laura W; Bartels, Meike; Vink, Jacqueline M; van Beijsterveldt, Catharina E M; Ligthart, Lannie; Boomsma, Dorret I; Middeldorp, Christel M

2017-06-21

Conduct problems in children and adolescents can predict antisocial personality disorder and related problems, such as crime and conviction. We sought an explanation for such predictions by performing a genetic longitudinal analysis. We estimated the effects of genetic, shared environmental, and unique environmental factors on variation in conduct problems measured at childhood and adolescence and antisocial personality problems measured at adulthood and on the covariation across ages. We also tested whether these estimates differed by sex. Longitudinal data were collected in the Netherlands Twin Register over a period of 27 years. Age appropriate and comparable measures of conduct and antisocial personality problems, assessed with the Achenbach System of Empirically Based Assessment, were available for 9783 9-10-year-old, 6839 13-18-year-old, and 7909 19-65-year-old twin pairs, respectively; 5114 twins have two or more assessments. At all ages, men scored higher than women. There were no sex differences in the estimates of the genetic and environmental influences. During childhood, genetic and environmental factors shared by children in families explained 43 and 44% of the variance of conduct problems, with the remaining variance due to unique environment. During adolescence and adulthood, genetic and unique environmental factors equally explained the variation. Longitudinal correlations across age varied between 0.20 and 0.38 and were mainly due to stable genetic factors. We conclude that shared environment is mainly of importance during childhood, while genetic factors contribute to variation in conduct and antisocial personality problems at all ages, and also underlie its stability over age.

Prediction of Child Performance on a Parent-Child Behavioral Approach Test with Animal Phobic Children

ERIC Educational Resources Information Center

Ollendick, Thomas H.; Lewis, Krystal M.; Cowart, Maria J. W.; Davis, Thompson, III

2012-01-01

A host of factors including genetic influences, temperament characteristics, learning experiences, information processing biases, parental psychopathology, and specific parenting practices have been hypothesized to contribute to the development and expression of children's phobias. In the present study, the authors focused on parental…

Genetics of forest trees

Treesearch

Jessica Wright

2014-01-01

Combining data from provenance test studies with our current understanding of predicted climate change can be a powerful tool for informing reforestation efforts. However, the limitations of both sources of data need to be understood to develop an approach to ecological restoration that reduces risk and promotes the highest chance of successful reforestation.

Scoring in genetically modified organism proficiency tests based on log-transformed results.

PubMed

Thompson, Michael; Ellison, Stephen L R; Owen, Linda; Mathieson, Kenneth; Powell, Joanne; Key, Pauline; Wood, Roger; Damant, Andrew P

2006-01-01

The study considers data from 2 UK-based proficiency schemes and includes data from a total of 29 rounds and 43 test materials over a period of 3 years. The results from the 2 schemes are similar and reinforce each other. The amplification process used in quantitative polymerase chain reaction determinations predicts a mixture of normal, binomial, and lognormal distributions dominated by the latter 2. As predicted, the study results consistently follow a positively skewed distribution. Log-transformation prior to calculating z-scores is effective in establishing near-symmetric distributions that are sufficiently close to normal to justify interpretation on the basis of the normal distribution.

Prediction of Unsteady Aerodynamic Coefficients at High Angles of Attack

NASA Technical Reports Server (NTRS)

Pamadi, Bandu N.; Murphy, Patrick C.; Klein, Vladislav; Brandon, Jay M.

2001-01-01

The nonlinear indicial response method is used to model the unsteady aerodynamic coefficients in the low speed longitudinal oscillatory wind tunnel test data of the 0.1 scale model of the F-16XL aircraft. Exponential functions are used to approximate the deficiency function in the indicial response. Using one set of oscillatory wind tunnel data and parameter identification method, the unknown parameters in the exponential functions are estimated. The genetic algorithm is used as a least square minimizing algorithm. The assumed model structures and parameter estimates are validated by comparing the predictions with other sets of available oscillatory wind tunnel test data.

Genetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue.

PubMed

Ackerman, Michael J

2015-11-01

Merriam-Webster's online dictionary defines purgatory as "an intermediate state after death for expiatory purification" or more specifically as "a place or state of punishment wherein according to Roman Catholic doctrine the souls of those who die in God׳s grace may make satisfaction for past sins and so become fit for heaven." Alternatively, it is defined as "a place or state of temporary suffering or misery." Either way, purgatory is a place where you are stuck, and you don't want to be stuck there. It is in this context that the term genetic purgatory is introduced. Genetic purgatory is a place where the genetic test-ordering physician and patients and their families are stuck when a variant of uncertain/unknown significance (VUS) has been elucidated. It is in this dark place where suffering and misery are occurring because of unenlightened handling of a VUS, which includes using the VUS for predictive genetic testing and making radical treatment recommendations based on the presence or absence of a so-called maybe mutation. Before one can escape from this miserable place, one must first recognize that one is stuck there. Hence, the purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticists/genetic counselors who order such genetic tests believers in genetic purgatory. Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Commercialization, patents and moral assessment of biotechnology products.

PubMed

Hoedemaekers, R

2001-06-01

The biotechnology patent debates have revealed deep moral concerns about basic genetics research, R&D and specific biotechnological products, concerns that are seldom taken into consideration in Technology Assessment. In this paper important moral concerns are examined which appear at the various stages of development of a specific genetic product: a predictive genetic test. The purpose is to illustrate the need for a more contextual approach in technology assessment, which integrates the various forms of interaction between bio-technology and society or societal segments. Such an approach will generate greater insight in the moral issues at all stages of a product's life-cycle and this will facilitate decision-making on the 'morality' of a specific biotechnological product.

Genetic diversity and trait genomic prediction in a pea diversity panel.

PubMed

Burstin, Judith; Salloignon, Pauline; Chabert-Martinello, Marianne; Magnin-Robert, Jean-Bernard; Siol, Mathieu; Jacquin, Françoise; Chauveau, Aurélie; Pont, Caroline; Aubert, Grégoire; Delaitre, Catherine; Truntzer, Caroline; Duc, Gérard

2015-02-21

Pea (Pisum sativum L.), a major pulse crop grown for its protein-rich seeds, is an important component of agroecological cropping systems in diverse regions of the world. New breeding challenges imposed by global climate change and new regulations urge pea breeders to undertake more efficient methods of selection and better take advantage of the large genetic diversity present in the Pisum sativum genepool. Diversity studies conducted so far in pea used Simple Sequence Repeat (SSR) and Retrotransposon Based Insertion Polymorphism (RBIP) markers. Recently, SNP marker panels have been developed that will be useful for genetic diversity assessment and marker-assisted selection. A collection of diverse pea accessions, including landraces and cultivars of garden, field or fodder peas as well as wild peas was characterised at the molecular level using newly developed SNP markers, as well as SSR markers and RBIP markers. The three types of markers were used to describe the structure of the collection and revealed different pictures of the genetic diversity among the collection. SSR showed the fastest rate of evolution and RBIP the slowest rate of evolution, pointing to their contrasted mode of evolution. SNP markers were then used to predict phenotypes -the date of flowering (BegFlo), the number of seeds per plant (Nseed) and thousand seed weight (TSW)- that were recorded for the collection. Different statistical methods were tested including the LASSO (Least Absolute Shrinkage ans Selection Operator), PLS (Partial Least Squares), SPLS (Sparse Partial Least Squares), Bayes A, Bayes B and GBLUP (Genomic Best Linear Unbiased Prediction) methods and the structure of the collection was taken into account in the prediction. Despite a limited number of 331 markers used for prediction, TSW was reliably predicted. The development of marker assisted selection has not reached its full potential in pea until now. This paper shows that the high-throughput SNP arrays that are being developed will most probably allow for a more efficient selection in this species.

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy

PubMed Central

Monga, Isha; Qureshi, Abid; Thakur, Nishant; Gupta, Amit Kumar; Kumar, Manoj

2017-01-01

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single-nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://crdd.osdd.net/servers/aspsirna/) covering three components viz (i) ASPsiDb, (ii) ASPsiPred, and (iii) analysis tools like ASP-siOffTar. ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Effmut) and wild-type allele (Effwild) with one mismatch by ASPsiPredSVM and ASPsiPredmatrix, respectively. In ASPsiPredSVM, 922 unique ASP-siRNAs with experimentally validated quantitative Effmut were used. During 10-fold cross-validation (10nCV) employing various sequence features on the training/testing dataset (T737), the best predictive model achieved a maximum Pearson’s correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Effmut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPredmatrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19 different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm, and off-target analysis tool that is expected to accelerate research in the field of RNAi-based therapeutics for human genetic diseases. PMID:28696921

Context-sensitive network-based disease genetics prediction and its implications in drug discovery.

PubMed

Chen, Yang; Xu, Rong

2017-04-01

Disease phenotype networks play an important role in computational approaches to identifying new disease-gene associations. Current disease phenotype networks often model disease relationships based on pairwise similarities, therefore ignore the specific context on how two diseases are connected. In this study, we propose a new strategy to model disease associations using context-sensitive networks (CSNs). We developed a CSN-based phenome-driven approach for disease genetics prediction, and investigated the translational potential of the predicted genes in drug discovery. We constructed CSNs by directly connecting diseases with associated phenotypes. Here, we constructed two CSNs using different data sources; the two networks contain 26 790 and 13 822 nodes respectively. We integrated the CSNs with a genetic functional relationship network and predicted disease genes using a network-based ranking algorithm. For comparison, we built Similarity-Based disease Networks (SBN) using the same disease phenotype data. In a de novo cross validation for 3324 diseases, the CSN-based approach significantly increased the average rank from top 12.6 to top 8.8% for all tested genes comparing with the SBN-based approach ( p

Literacy outcomes of children with early childhood speech sound disorders: impact of endophenotypes.

PubMed

Lewis, Barbara A; Avrich, Allison A; Freebairn, Lisa A; Hansen, Amy J; Sucheston, Lara E; Kuo, Iris; Taylor, H Gerry; Iyengar, Sudha K; Stein, Catherine M

2011-12-01

To demonstrate that early childhood speech sound disorders (SSD) and later school-age reading, written expression, and spelling skills are influenced by shared endophenotypes that may be in part genetic. Children with SSD and their siblings were assessed at early childhood (ages 4-6 years) and followed at school age (7-12 years). The relationship of shared endophenotypes with early childhood SSD and school-age outcomes and the shared genetic influences on these outcomes were examined. Structural equation modeling demonstrated that oral motor skills, phonological awareness, phonological memory, vocabulary, and speeded naming have varying influences on reading decoding, spelling, spoken language, and written expression at school age. Genetic linkage studies demonstrated linkage for reading, spelling, and written expression measures to regions on chromosomes 1, 3, 6, and 15 that were previously linked to oral motor skills, articulation, phonological memory, and vocabulary at early childhood testing. Endophenotypes predict school-age literacy outcomes over and above that predicted by clinical diagnoses of SSD or language impairment. Findings suggest that these shared endophenotypes and common genetic influences affect early childhood SSD and later school-age reading, spelling, spoken language, and written expression skills.

A Bayesian phylogenetic approach to estimating the stability of linguistic features and the genetic biasing of tone.

PubMed

Dediu, Dan

2011-02-07

Language is a hallmark of our species and understanding linguistic diversity is an area of major interest. Genetic factors influencing the cultural transmission of language provide a powerful and elegant explanation for aspects of the present day linguistic diversity and a window into the emergence and evolution of language. In particular, it has recently been proposed that linguistic tone-the usage of voice pitch to convey lexical and grammatical meaning-is biased by two genes involved in brain growth and development, ASPM and Microcephalin. This hypothesis predicts that tone is a stable characteristic of language because of its 'genetic anchoring'. The present paper tests this prediction using a Bayesian phylogenetic framework applied to a large set of linguistic features and language families, using multiple software implementations, data codings, stability estimations, linguistic classifications and outgroup choices. The results of these different methods and datasets show a large agreement, suggesting that this approach produces reliable estimates of the stability of linguistic data. Moreover, linguistic tone is found to be stable across methods and datasets, providing suggestive support for the hypothesis of genetic influences on its distribution.

Literacy Outcomes of Children With Early Childhood Speech Sound Disorders: Impact of Endophenotypes

PubMed Central

Lewis, Barbara A.; Avrich, Allison A.; Freebairn, Lisa A.; Hansen, Amy J.; Sucheston, Lara E.; Kuo, Iris; Taylor, H. Gerry; Iyengar, Sudha K.; Stein, Catherine M.

2012-01-01

Purpose To demonstrate that early childhood speech sound disorders (SSD) and later school-age reading, written expression, and spelling skills are influenced by shared endophenotypes that may be in part genetic. Method Children with SSD and their siblings were assessed at early childhood (ages 4–6 years) and followed at school age (7–12 years). The relationship of shared endophenotypes with early childhood SSD and school-age outcomes and the shared genetic influences on these outcomes were examined. Results Structural equation modeling demonstrated that oral motor skills, phonological awareness, phonological memory, vocabulary, and speeded naming have varying influences on reading decoding, spelling, spoken language, and written expression at school age. Genetic linkage studies demonstrated linkage for reading, spelling, and written expression measures to regions on chromosomes 1, 3, 6, and 15 that were previously linked to oral motor skills, articulation, phonological memory, and vocabulary at early childhood testing. Conclusions Endophenotypes predict school-age literacy outcomes over and above that predicted by clinical diagnoses of SSD or language impairment. Findings suggest that these shared endophenotypes and common genetic influences affect early childhood SSD and later school-age reading, spelling, spoken language, and written expression skills. PMID:21930616

Association of FKBP5 Polymorphisms and Childhood Abuse With Risk of Posttraumatic Stress Disorder Symptoms in Adults

PubMed Central

Binder, Elisabeth B.; Bradley, Rebekah G.; Liu, Wei; Epstein, Michael P.; Deveau, Todd C.; Mercer, Kristina B.; Tang, Yilang; Gillespie, Charles F.; Heim, Christine M.; Nemeroff, Charles B.; Schwartz, Ann C.; Cubells, Joseph F.; Ressler, Kerry J.

2008-01-01

Context In addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability. Objective To increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene × environment interactions of child abuse, level of non–child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5. Design, Setting, and Participants A cross-sectional study examining genetic and psychological risk factors in 900 non psychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non–child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007. Main Outcome Measures Severity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non–child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus. Results Level of child abuse and non–child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs ≥2 types of abuse, 20.93 [14.32]; and for no non–child abuse trauma, 3.58 [6.27] vs ≥4 types, 16.74 [12.90]; P<.001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non–child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P=.0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene × environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non–child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test. Conclusions Four SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non–child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD. PMID:18349090

Predicting Phenotypes from Genetic Crosses: A Mathematical Concept to Help Struggling Biology Students

ERIC Educational Resources Information Center

Baurhoo, Neerusha; Darwish, Shireef

2012-01-01

Predicting phenotypic outcomes from genetic crosses is often very difficult for biology students, especially those with learning disabilities. With our mathematical concept, struggling students in inclusive biology classrooms are now better equipped to solve genetic problems and predict phenotypes, because of improved understanding of dominance…

Intergenerational predictors of birth weight in the Philippines: correlations with mother's and father's birth weight and test of maternal constraint.

PubMed

Kuzawa, Christopher W; Eisenberg, Dan T A

2012-01-01

Birth weight (BW) predicts many health outcomes, but the relative contributions of genes and environmental factors to BW remain uncertain. Some studies report stronger mother-offspring than father-offspring BW correlations, with attenuated father-offspring BW correlations when the mother is stunted. These findings have been interpreted as evidence that maternal genetic or environmental factors play an important role in determining birth size, with small maternal size constraining paternal genetic contributions to offspring BW. Here we evaluate mother-offspring and father-offspring birth weight (BW) associations and evaluate whether maternal stunting constrains genetic contributions to offspring birth size. Data include BW of offspring (n = 1,101) born to female members (n = 382) and spouses of male members (n = 275) of a birth cohort (born 1983-84) in Metropolitan Cebu, Philippines. Regression was used to relate parental and offspring BW adjusting for confounders. Resampling testing was used to evaluate whether false paternity could explain any evidence for excess matrilineal inheritance. In a pooled model adjusting for maternal height and confounders, parental BW was a borderline-significantly stronger predictor of offspring BW in mothers compared to fathers (sex of parent interaction p = 0.068). In separate multivariate models, each kg in mother's and father's BW predicted a 271±53 g (p<0.00001) and 132±55 g (p = 0.017) increase in offspring BW, respectively. Resampling statistics suggested that false paternity rates of >25% and likely 50% would be needed to explain these differences. There was no interaction between maternal stature and maternal BW (interaction p = 0.520) or paternal BW (p = 0.545). Each kg change in mother's BW predicted twice the change in offspring BW as predicted by a change in father's BW, consistent with an intergenerational maternal effect on offspring BW. Evidence for excess matrilineal BW heritability at all levels of maternal stature points to indirect genetic, mitochondrial, or epigenetic maternal contributions to offspring fetal growth.

Open sharing of genomic data: Who does it and why?

PubMed

Haeusermann, Tobias; Greshake, Bastian; Blasimme, Alessandro; Irdam, Darja; Richards, Martin; Vayena, Effy

2017-01-01

We explored the characteristics and motivations of people who, having obtained their genetic or genomic data from Direct-To-Consumer genetic testing (DTC-GT) companies, voluntarily decide to share them on the publicly accessible web platform openSNP. The study is the first attempt to describe open data sharing activities undertaken by individuals without institutional oversight. In the paper we provide a detailed overview of the distribution of the demographic characteristics and motivations of people engaged in genetic or genomic open data sharing. The geographical distribution of the respondents showed the USA as dominant. There was no significant gender divide, the age distribution was broad, educational background varied and respondents with and without children were equally represented. Health, even though prominent, was not the respondents' primary or only motivation to be tested. As to their motivations to openly share their data, 86.05% indicated wanting to learn about themselves as relevant, followed by contributing to the advancement of medical research (80.30%), improving the predictability of genetic testing (76.02%) and considering it fun to explore genotype and phenotype data (75.51%). Whereas most respondents were well aware of the privacy risks of their involvement in open genetic data sharing and considered the possibility of direct, personal repercussions troubling, they estimated the risk of this happening to be negligible. Our findings highlight the diversity of DTC-GT consumers who decide to openly share their data. Instead of focusing exclusively on health-related aspects of genetic testing and data sharing, our study emphasizes the importance of taking into account benefits and risks that stretch beyond the health spectrum. Our results thus lend further support to the call for a broader and multi-faceted conceptualization of genomic utility.

Polygenic risk and the development and course of asthma: Evidence from a 4-decade longitudinal study

PubMed Central

Belsky, DW; Sears, MR; Hancox, RJ; Harrington, HL; Houts, R; Moffitt, TE; Sugden, K; Williams, B; Poulton, R; Caspi, A

2013-01-01

BACKGROUND Genome-wide association studies (GWAS) have discovered loci that predispose to asthma. To integrate these new discoveries with emerging models of asthma pathobiology, research is needed to test how genetic discoveries relate to developmental and biological characteristics of asthma. METHODS We derived a multi-locus profile of genetic risk from published GWAS of asthma case status. We then tested associations between this “genetic risk score” and developmental and biological characteristics of asthma in a population-based long-running birth cohort, the Dunedin Longitudinal Study (n=1,037). We evaluated asthma onset, persistence, atopy, airway hyperresponsiveness, incompletely reversible airflow obstruction, and asthma-related school and work absenteeism and hospitalization during 9 prospective assessments spanning ages 9–38 years, when 95% of surviving cohort members were seen. INTERPRETATION Cohort members at higher genetic risk experienced asthma onset earlier in life (HR=1.12 [1.01–1.26]). Childhood-onset asthma cases at higher genetic risk were more likely to become life-course-persistent asthma cases (RR=1.36 [1.14–1.63]). Asthma cases at higher genetic risk more often manifested atopy (RR=1.07 [1.01–1.14]), airway hyperresponsiveness (RR=1.16 [1.03–1.32]), and incompletely reversible airflow obstruction (RR=1.28 [1.04–1.57]). They were also more likely to miss school or work due to asthma (IRR=1.38 [1.02–1.86]) and to be hospitalized with breathing problems (HR=1.38 [1.07–1.79]). Genotypic information about asthma risk was independent of and additive to information derived from cohort members’ family histories of asthma. CONCLUSIONS Findings from this population study confirm that GWAS-discoveries for asthma associate with a childhood-onset phenotype and advance asthma genetics beyond the original GWAS-discoveries in three ways: (1) We show that genetic risks predict which childhood-onset asthma cases remit and which become life-course-persistent cases, although these predictions are not sufficiently sensitive or specific to support immediate clinical translation; (2) We elucidate a biological profile of the asthma that arises from these genetic risks: asthma characterized by atopy and airway hyperresponsiveness and leading to incompletely reversible airflow obstruction; and (3) We describe the real-life impact of GWAS-discoveries by quantifying genetic associations with missed school and work and hospitalization. PMID:24429243

In silico prediction of toxicity of phenols to Tetrahymena pyriformis by using genetic algorithm and decision tree-based modeling approach.

PubMed

Abbasitabar, Fatemeh; Zare-Shahabadi, Vahid

2017-04-01

Risk assessment of chemicals is an important issue in environmental protection; however, there is a huge lack of experimental data for a large number of end-points. The experimental determination of toxicity of chemicals involves high costs and time-consuming process. In silico tools such as quantitative structure-toxicity relationship (QSTR) models, which are constructed on the basis of computational molecular descriptors, can predict missing data for toxic end-points for existing or even not yet synthesized chemicals. Phenol derivatives are known to be aquatic pollutants. With this background, we aimed to develop an accurate and reliable QSTR model for the prediction of toxicity of 206 phenols to Tetrahymena pyriformis. A multiple linear regression (MLR)-based QSTR was obtained using a powerful descriptor selection tool named Memorized_ACO algorithm. Statistical parameters of the model were 0.72 and 0.68 for R training 2 and R test 2 , respectively. To develop a high-quality QSTR model, classification and regression tree (CART) was employed. Two approaches were considered: (1) phenols were classified into different modes of action using CART and (2) the phenols in the training set were partitioned to several subsets by a tree in such a manner that in each subset, a high-quality MLR could be developed. For the first approach, the statistical parameters of the resultant QSTR model were improved to 0.83 and 0.75 for R training 2 and R test 2 , respectively. Genetic algorithm was employed in the second approach to obtain an optimal tree, and it was shown that the final QSTR model provided excellent prediction accuracy for the training and test sets (R training 2 and R test 2 were 0.91 and 0.93, respectively). The mean absolute error for the test set was computed as 0.1615. Copyright © 2016 Elsevier Ltd. All rights reserved.

miR-8-3p regulates mitoferrin in the testes of Bactrocera dorsalis to ensure normal spermatogenesis

PubMed Central

Tariq, Kaleem; Metzendorf, Christoph; Peng, Wei; Sohail, Summar; Zhang, Hongyu

2016-01-01

Genetics-enhanced sterile insect techniques (SIT) are promising novel approaches to control Bactrocera dorsalis, the most destructive horticultural pest in East Asia and the Pacific region. To identify novel genetic agents to alter male fertility of B. dorsalis, previous studies investigated miRNA expression in testes of B. dorsalis. One miRNA, miR-8-3p was predicted to bind the 3′UTR of putative B. dorsalis mitoferrin (bmfrn). The ortholog of bmfrn in D. melanogaster is essential for male fertility. Here we show that bmfrn has all conserved amino acid residues of known mitoferrins and is most abundantly expressed in B. dorsalis testes, making miR-8-3p and mitoferrin candidates for genetics-enhanced SIT. Furthermore, using a dual-luciferase reporter system, we show in HeLa cells that miR-8-3p interacts with the 3′UTR of bmfrn. Dietary treatments of adult male flies with miR-8-3p mimic, antagomiR, or bmfrn dsRNA, altered mitoferrin expression in the testes and resulted in reduced male reproductive capacity due to reduced numbers and viability of spermatozoa. We show for the first time that a mitoferrin is regulated by a miRNA and we demonstrate miR-8-3p as well as bmfrn dsRNA to be promising novel agents that could be used for genetics-enhanced SIT. PMID:26932747

Ethical issues in the use of genetic testing of patients with schizophrenia and their families.

PubMed

DeLisi, Lynn E

2014-05-01

This review outlines the positive and negative aspects of DNA testing and provides an account of the issues particularly relevant to schizophrenia. Modern technology has changed the field of medicine so rapidly that patients and their families have become much more independent in their healthcare decisions than in the previous decade. Simply by finding information on the Internet, they gain knowledge about disease diagnosis, treatment options and their side-effects. No medical field likely has been more affected and more controversial than that of genetics. It is now possible to sequence the individual human genome and detect single nucleotide variations, microdeletions and duplications within it. Commercial companies have sprung up in a similar manner to the software or electronic industries and have begun to market direct-to-consumer DNA testing. Much of this may be performed to satisfy curiosity about one's ancestry; but commercially available results that appear incidentally can also be distributed to the consumer. Ethicists, genetics researchers, clinicians and government agencies are currently in discussion about concerns raised about commercially available DNA testing, while at the same time recognizing its value in some instances to be able to predict very serious disabilities.

Internet-Based Direct-to-Consumer Genetic Testing: A Systematic Review.

PubMed

Covolo, Loredana; Rubinelli, Sara; Ceretti, Elisabetta; Gelatti, Umberto

2015-12-14

Direct-to-consumer genetic tests (DTC-GT) are easily purchased through the Internet, independent of a physician referral or approval for testing, allowing the retrieval of genetic information outside the clinical context. There is a broad debate about the testing validity, their impact on individuals, and what people know and perceive about them. The aim of this review was to collect evidence on DTC-GT from a comprehensive perspective that unravels the complexity of the phenomenon. A systematic search was carried out through PubMed, Web of Knowledge, and Embase, in addition to Google Scholar according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist with the key term "Direct-to-consumer genetic test." In the final sample, 118 articles were identified. Articles were summarized in five categories according to their focus on (1) knowledge of, attitude toward use of, and perception of DTC-GT (n=37), (2) the impact of genetic risk information on users (n=37), (3) the opinion of health professionals (n=20), (4) the content of websites selling DTC-GT (n=16), and (5) the scientific evidence and clinical utility of the tests (n=14). Most of the articles analyzed the attitude, knowledge, and perception of DTC-GT, highlighting an interest in using DTC-GT, along with the need for a health care professional to help interpret the results. The articles investigating the content analysis of the websites selling these tests are in agreement that the information provided by the companies about genetic testing is not completely comprehensive for the consumer. Given that risk information can modify consumers' health behavior, there are surprisingly few studies carried out on actual consumers and they do not confirm the overall concerns on the possible impact of DTC-GT. Data from studies that investigate the quality of the tests offered confirm that they are not informative, have little predictive power, and do not measure genetic risk appropriately. The impact of DTC-GT on consumers' health perceptions and behaviors is an emerging concern. However, negative effects on consumers or health benefits have yet to be observed. Nevertheless, since the online market of DTC-GT is expected to grow, it is important to remain aware of a possible impact.

Internet-Based Direct-to-Consumer Genetic Testing: A Systematic Review

PubMed Central

Rubinelli, Sara; Ceretti, Elisabetta; Gelatti, Umberto

2015-01-01

Background Direct-to-consumer genetic tests (DTC-GT) are easily purchased through the Internet, independent of a physician referral or approval for testing, allowing the retrieval of genetic information outside the clinical context. There is a broad debate about the testing validity, their impact on individuals, and what people know and perceive about them. Objective The aim of this review was to collect evidence on DTC-GT from a comprehensive perspective that unravels the complexity of the phenomenon. Methods A systematic search was carried out through PubMed, Web of Knowledge, and Embase, in addition to Google Scholar according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist with the key term “Direct-to-consumer genetic test.” Results In the final sample, 118 articles were identified. Articles were summarized in five categories according to their focus on (1) knowledge of, attitude toward use of, and perception of DTC-GT (n=37), (2) the impact of genetic risk information on users (n=37), (3) the opinion of health professionals (n=20), (4) the content of websites selling DTC-GT (n=16), and (5) the scientific evidence and clinical utility of the tests (n=14). Most of the articles analyzed the attitude, knowledge, and perception of DTC-GT, highlighting an interest in using DTC-GT, along with the need for a health care professional to help interpret the results. The articles investigating the content analysis of the websites selling these tests are in agreement that the information provided by the companies about genetic testing is not completely comprehensive for the consumer. Given that risk information can modify consumers’ health behavior, there are surprisingly few studies carried out on actual consumers and they do not confirm the overall concerns on the possible impact of DTC-GT. Data from studies that investigate the quality of the tests offered confirm that they are not informative, have little predictive power, and do not measure genetic risk appropriately. Conclusions The impact of DTC-GT on consumers’ health perceptions and behaviors is an emerging concern. However, negative effects on consumers or health benefits have yet to be observed. Nevertheless, since the online market of DTC-GT is expected to grow, it is important to remain aware of a possible impact. PMID:26677835

Constraints on decision making: implications from genetics, personality, and addiction.

PubMed

Baker, Travis E; Stockwell, Tim; Holroyd, Clay B

2013-09-01

An influential neurocomputational theory of the biological mechanisms of decision making, the "basal ganglia go/no-go model," holds that individual variability in decision making is determined by differences in the makeup of a striatal system for approach and avoidance learning. The model has been tested empirically with the probabilistic selection task (PST), which determines whether individuals learn better from positive or negative feedback. In accordance with the model, in the present study we examined whether an individual's ability to learn from positive and negative reinforcement can be predicted by genetic factors related to the midbrain dopamine system. We also asked whether psychiatric and personality factors related to substance dependence and dopamine affect PST performance. Although we found characteristics that predicted individual differences in approach versus avoidance learning, these observations were qualified by additional findings that appear inconsistent with the predictions of the go/no-go model. These results highlight a need for future research to validate the PST as a measure of basal ganglia reward learning.

Testing the genetic predictions of a biogeographical model in a dominant endemic Eastern Pacific coral (Porites panamensis) using a genetic seascape approach

PubMed Central

Saavedra-Sotelo, Nancy C; Calderon-Aguilera, Luis E; Reyes-Bonilla, Héctor; Paz-García, David A; López-Pérez, Ramón A; Cupul-Magaña, Amilcar; Cruz-Barraza, José A; Rocha-Olivares, Axayácatl

2013-01-01

The coral fauna of the Eastern Tropical Pacific (ETP) is depauperate and peripheral; hence, it has drawn attention to the factors allowing its survival. Here, we use a genetic seascape approach and ecological niche modeling to unravel the environmental factors correlating with the genetic variation of Porites panamensis, a hermatypic coral endemic to the ETP. Specifically, we test if levels of diversity and connectivity are higher among abundant than among depauperate populations, as expected by a geographically relaxed version of the Abundant Center Hypothesis (rel-ACH). Unlike the original ACH, referring to a geographical center of distribution of maximal abundance, the rel-ACH refers only to a center of maximum abundance, irrespective of its geographic position. The patterns of relative abundance of P. panamensis in the Mexican Pacific revealed that northern populations from Baja California represent its center of abundance; and southern depauperate populations along the continental margin are peripheral relative to it. Genetic patterns of diversity and structure of nuclear DNA sequences (ribosomal DNA and a single copy open reading frame) and five alloenzymatic loci partially agreed with rel-ACH predictions. We found higher diversity levels in peninsular populations and significant differentiation between peninsular and continental colonies. In addition, continental populations showed higher levels of differentiation and lower connectivity than peninsular populations in the absence of isolation by distance in each region. Some discrepancies with model expectations may relate to the influence of significant habitat discontinuities in the face of limited dispersal potential. Environmental data analyses and niche modeling allowed us to identify temperature, water clarity, and substrate availability as the main factors correlating with patterns of abundance, genetic diversity, and structure, which may hold the key to the survival of P. panamensis in the face of widespread environmental degradation. PMID:24324860

A multifactorial analysis of obesity as CVD risk factor: use of neural network based methods in a nutrigenetics context.

PubMed

Valavanis, Ioannis K; Mougiakakou, Stavroula G; Grimaldi, Keith A; Nikita, Konstantina S

2010-09-08

Obesity is a multifactorial trait, which comprises an independent risk factor for cardiovascular disease (CVD). The aim of the current work is to study the complex etiology beneath obesity and identify genetic variations and/or factors related to nutrition that contribute to its variability. To this end, a set of more than 2300 white subjects who participated in a nutrigenetics study was used. For each subject a total of 63 factors describing genetic variants related to CVD (24 in total), gender, and nutrition (38 in total), e.g. average daily intake in calories and cholesterol, were measured. Each subject was categorized according to body mass index (BMI) as normal (BMI ≤ 25) or overweight (BMI > 25). Two artificial neural network (ANN) based methods were designed and used towards the analysis of the available data. These corresponded to i) a multi-layer feed-forward ANN combined with a parameter decreasing method (PDM-ANN), and ii) a multi-layer feed-forward ANN trained by a hybrid method (GA-ANN) which combines genetic algorithms and the popular back-propagation training algorithm. PDM-ANN and GA-ANN were comparatively assessed in terms of their ability to identify the most important factors among the initial 63 variables describing genetic variations, nutrition and gender, able to classify a subject into one of the BMI related classes: normal and overweight. The methods were designed and evaluated using appropriate training and testing sets provided by 3-fold Cross Validation (3-CV) resampling. Classification accuracy, sensitivity, specificity and area under receiver operating characteristics curve were utilized to evaluate the resulted predictive ANN models. The most parsimonious set of factors was obtained by the GA-ANN method and included gender, six genetic variations and 18 nutrition-related variables. The corresponding predictive model was characterized by a mean accuracy equal of 61.46% in the 3-CV testing sets. The ANN based methods revealed factors that interactively contribute to obesity trait and provided predictive models with a promising generalization ability. In general, results showed that ANNs and their hybrids can provide useful tools for the study of complex traits in the context of nutrigenetics.

Optimized testing schemes using nucleus progeny, adult MOET siblings, or juvenile MOET pedigrees in dairy cattle closed populations.

PubMed

Bondoc, O L; Smith, C

1993-01-12

Selection response rates are predicted for nucleus progeny testing, adult multiple ovulation and embryo transfer (MOET) sib testing, and juvenile MOET pedigree testing in closed populations. Deterministic models are adapted to adjust predicted genetic gains for the effects of population size and structure, selection disequilibrium, sampling losses, and inbreeding depression. The improvement schemes were optimized for different numbers of sires used and first lactation females recorded per year. The number of nucleus daughters tested per sire, and of females per MOET full sibship, that maximize the predicted response to selection per year, were determined. Annual genetic gains and inbreeding rates were interpolated to the same planning horizon (20 years) to compare the optimized schemes for a wide range of situations. The predicted maximum genetic gain per year is higher for adult MOET than for juvenile MOET (due to the proportional extra time to collect the embryos needed) and for nucleus progeny testing. Average annual inbreeding rates are much higher for MOET schemes than for nucleus progeny testing. The advantages of adult and juvenile over nucleus progeny testing are little affected by planning horizon, but are higher with more females recorded per year, higher heritability, and higher reproductive and MOET success rates. Comparison of the schemes at the same level of inbreeding is fairer for fixed testing resources. At the same inbreeding level, the genetic advantage of adult MOET was generally maintained, but juvenile MOET then lost its advantage over progeny testing in these closed populations. ZUSAMMENFASSUNG: Optimierte Prüfpläne für Nukleusnachkommen, adulte MOET Geschwister oder juvenile MOET Pedigrees in geschlossenen Milchviehpopulationen Selektionserfolge werden für Nukleusnachkommenprüfung, adulte multiple Ovulation (MOET) und Embryotransfer, Geschwisterprüfung und juvenile MOET Pedigreeprüfung geschlossener Populationen geschätzt. Deterministische Modelle werden modifiziert zur Berücksichtigung geschätzter genetischer Fortschritte für die Wirkungen von Populationsgröße, Struktur, Selektionsungleichgewicht, Stichprobenungenauigkeit und Inzuchtdepression. Die Zuchtpläne werden für verschiedene Zahlen von Stieren und Erstlaktationskühe pro Jahr optimiert. Die Zahl der geprüften Nukleustöchter je Stier und Kühe je MOETVollgeschwistergruppe, die den geschätzten Erfolg maximieren, werden bestimmt. Um die optimierten Pläne über einen weiten Bereich zu vergleichen, werden jährlicher Zuchtfortschritt und Inzuchtzuwachs für den gleichen Planungshorizont von 20 Jahren interpoliert. Der geschätzte maximale Zuchtfortschritt pro Jahr ist für adultes MOET höher als bei juvenilem (wegen zusätzlicher Zeit zur Embryonengewinnung) und bei Nukleusnachkommenschaftsprüfung. Durchschnittliche jährliche Inzuchtraten sind viel höher für MOET Pläne als für das Nachkommenschaftsprüfsystem. Die Vorteile des adulten und juvenilen MOET über Nukleusnachkommenprüfung werden durch den Planungshorizont nur geringfügig tangiert, werden aber höher, wenn mehr weibliche Tiere je Jahr geprüft werden bei höherer Heritabilität, höherer Reproduktions- und Erfolgsrate. Der Vergleich der Pläne beim gleichen Inzuchtniveau ist für gegebene Testresourcen angemessener. 1993 Blackwell Verlag GmbH.

Genetic parameters for lactose and its correlation with other milk production traits and fitness traits in pasture-based production systems.

PubMed

Haile-Mariam, M; Pryce, J E

2017-05-01

Lactose is a major component of milk (typically around 5% of composition) that is not usually directly considered in national genetic improvement programs of dairy cattle. Daily test-day lactose yields and percentage data from pasture-based seasonal calving herds in Australia were analyzed to assess if lactose content can be used for predicting fitness traits and if an additional benefit is achieved by including lactose yield in selecting for milk yield traits. Data on lactose percentage collected from 2007 to 2014, from about 600 herds, were used to estimated genetic parameters for lactose percentage and lactose yield and correlations with other milk yield traits, somatic cell count (SCC), calving interval (CIV), and survival. Daily test-day data were analyzed using bivariate random regression models. In addition, multi-trait models were also performed mainly to assess the value of lactose to predict fitness traits. The heritability of lactose percentage (0.25 to 0.37) was higher than lactose yield (0.11 to 0.20) in the first parity. Genetically, the correlation of lactose percentage with protein percentage varied from 0.3 at the beginning of lactation to -0.24 at the end of the lactation in the first parity. Similar patterns in genetic correlations were also observed in the second and third parity. At all levels (i.e., genetic, permanent environmental, and residual), the correlation between milk yield and lactose yield was close to 1. The genetic and permanent environmental correlations between lactose percentage and SCC were stronger in the second and third parity and toward the end of the lactation (-0.35 to -0.50) when SCC levels are at their maximum. The genetic correlation between lactose percentage in the first 120 d and CIV (-0.23) was similar to correlation of CIV with protein percentage (-0.28), another component trait with the potential to predict fertility. Furthermore, the correlations of estimated breeding values of lactose percentage and estimated breeding values of traits such as survival, fertility, SCC, and angularity suggest that the value of lactose percentage as a predictor of fitness traits is weak. The results also suggest that including lactose yield as a trait into the breeding objective is of limited value due to the high positive genetic correlation between lactose yield and protein yield, the trait highly emphasized in Australia. However, recording lactose percentage as part of the routine milk recording system will enable the Australian dairy industry to respond quickly to any future changes and market signals. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Novel Applications of Multi-task Learning and Multiple Output Regression to Multiple Genetic Trait Prediction

USDA-ARS?s Scientific Manuscript database

Given a set of biallelic molecular markers, such as SNPs, with genotype values encoded numerically on a collection of plant, animal or human samples, the goal of genetic trait prediction is to predict the quantitative trait values by simultaneously modeling all marker effects. Genetic trait predicti...

PhenoVar: a phenotype-driven approach in clinical genomics for the diagnosis of polymalformative syndromes

PubMed Central

2014-01-01

Background We propose a phenotype-driven analysis of encrypted exome data to facilitate the widespread implementation of exome sequencing as a clinical genetic screening test. Twenty test-patients with varied syndromes were selected from the literature. For each patient, the mutation, phenotypic data, and genetic diagnosis were available. Next, control exome-files, each modified to include one of these twenty mutations, were assigned to the corresponding test-patients. These data were used by a geneticist blinded to the diagnoses to test the efficiency of our software, PhenoVar. The score assigned by PhenoVar to any genetic diagnosis listed in OMIM (Online Mendelian Inheritance in Man) took into consideration both the patient’s phenotype and all variations present in the corresponding exome. The physician did not have access to the individual mutations. PhenoVar filtered the search using a cut-off phenotypic match threshold to prevent undesired discovery of incidental findings and ranked the OMIM entries according to diagnostic score. Results When assigning the same weight to all variants in the exome, PhenoVar predicted the correct diagnosis in 10/20 patients, while in 15/20 the correct diagnosis was among the 4 highest ranked diagnoses. When assigning a higher weight to variants known, or bioinformatically predicted, to cause disease, PhenoVar’s yield increased to 14/20 (18/20 in top 4). No incidental findings were identified using our cut-off phenotypic threshold. Conclusion The phenotype-driven approach described could render widespread use of ES more practical, ethical and clinically useful. The implications about novel disease identification, advancement of complex diseases and personalized medicine are discussed. PMID:24884844

Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

PubMed Central

Diaz-Cano, Salvador J.

2012-01-01

Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning. PMID:22408433

Patient and Genetic Counselor Perceptions of In-person versus Telephone Genetic Counseling for Hereditary Breast/Ovarian Cancer

PubMed Central

Jacobs, Aryana S.; Schwartz, Marc D.; Valdimarsdottir, Heiddis; Nusbaum, Rachel H.; Hooker, Gillian W.; DeMarco, Tiffani A.; Heinzmann, Jessica E.; McKinnon, Wendy; McCormick, Shelley R.; Davis, Claire; Forman, Andrea D.; Lebensohn, Alexandra Perez; Dalton, Emily; Tully, Diana Moglia; Graves, Kristi D.; Similuk, Morgan; Kelly, Scott; Peshkin, Beth N.

2016-01-01

Telephone genetic counseling (TC) for high-risk women interested in BRCA1/2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5-item genetic counselor process questionnaire (GCQ) assessing key elements of pre-test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision- making) with the 479 female participants (TC, N=236; UC, N=243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11, p = 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (β = 0.172, p<0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21, p=0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non-Hispanic Whites). We discuss other potential clinical and research implications of our findings. PMID:26969308

Personality Polygenes, Positive Affect, and Life Satisfaction

PubMed Central

Weiss, Alexander; Baselmans, Bart M. L.; Hofer, Edith; Yang, Jingyun; Okbay, Aysu; Lind, Penelope A.; Miller, Mike B.; Nolte, Ilja M.; Zhao, Wei; Hagenaars, Saskia P.; Hottenga, Jouke-Jan; Matteson, Lindsay K.; Snieder, Harold; Faul, Jessica D.; Hartman, Catharina A.; Boyle, Patricia A.; Tiemeier, Henning; Mosing, Miriam A.; Pattie, Alison; Davies, Gail; Liewald, David C.; Schmidt, Reinhold; De Jager, Philip L.; Heath, Andrew C.; Jokela, Markus; Starr, John M.; Oldehinkel, Albertine J.; Johannesson, Magnus; Cesarini, David; Hofman, Albert; Harris, Sarah E.; Smith, Jennifer A.; Keltikangas-Järvinen, Liisa; Pulkki-Råback, Laura; Schmidt, Helena; Smith, Jacqui; Iacono, William G.; McGue, Matt; Bennett, David A.; Pedersen, Nancy L.; Magnusson, Patrik K. E.; Deary, Ian J.; Martin, Nicholas G.; Boomsma, Dorret I.; Bartels, Meike; Luciano, Michelle

2016-01-01

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of −0.49 and −0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains. PMID:27546527

Associations of triglyceride levels with longevity and frailty: A Mendelian randomization analysis

PubMed Central

Liu, Zuyun; Burgess, Stephen; Wang, Zhengdong; Deng, Wan; Chu, Xuefeng; Cai, Jian; Zhu, Yinsheng; Shi, Jianming; Xie, Xuejuan; Wang, Yong; Jin, Li; Wang, Xiaofeng

2017-01-01

Observational studies suggest associations of triglyceride levels with longevity and frailty. This study aimed to test whether the associations are causal. We used data from the Rugao Longevity and Ageing Study, a population-based cohort study performed in Rugao, China. A variant in the APOA5 gene region (rs662799) was used as the genetic instrument. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted triglycerides with two ageing phenotypes – longevity ( ≥95 years) and frailty (modified Fried frailty phenotype and Rockwood frailty index). C allele of rs662799 was robustly associated with higher triglyceride levels in the comparison group (β = 0.301 mmol/L per allele, p < 0.001), with an F statistic of 95.3 and R2 = 0.040. However MR analysis did not provide strong evidence for an association between genetically predicted triglyceride levels and probability of longevity (OR: 0.61; 95% CI: 0.35, 1.07 per 1 mmol/L increase in triglycerides). In the ageing arm (70–84 years), genetically predicted triglyceride levels were not associated with the frailty index (β = 0.008; 95% CI: −0.013, 0.029) or the frailty phenotype (OR: 1.91; 95% CI: 0.84, 4.37). In conclusion, there is currently a lack of sufficient evidence to support causal associations of triglyceride levels with longevity and frailty in elderly populations. PMID:28134330

In Silico Detection of Sequence Variations Modifying Transcriptional Regulation

PubMed Central

Andersen, Malin C; Engström, Pär G; Lithwick, Stuart; Arenillas, David; Eriksson, Per; Lenhard, Boris; Wasserman, Wyeth W; Odeberg, Jacob

2008-01-01

Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation. PMID:18208319

Reproductive health and genetic testing in the Third World.

PubMed

Penchaszadeh, V B

1993-09-01

New reproductive genetics means recently developed techniques to prevent the birth of children with specific defects or genetic diseases by testing individuals for sickle cell anemia, the thalassemias, Tay-Sachs disease, cystic fibrosis, or Down syndrome. Third World health services have many deficiencies with high maternal mortality rates (30-40 fold higher than in developed countries), the low percentage of births delivered by health personnel, the high rates of low birth weight babies, and high child malnutrition and infant mortality rates. The main issues in women's reproductive health are fertility regulation, abortion, maternal mortality, sexually transmitted diseases, and infertility. As a result of expansion in contraceptive use worldwide, the total fertility rate in developing countries has declined from 6.1 in 1965 to 3.9 in 1990. It is estimated that, worldwide, 36-53 million induced abortions are performed each year, most of them in developing nations. WHO estimates that more than 500,000 women die each year because of complications of pregnancy, most in developing countries. More than 95% of the 13 million estimated deaths of children under 5 years of age have occurred in these countries. Approximately 200 million people carry a potentially pathologic hemoglobinopathy gene, and about 250,000 children are born every year with hemoglobinopathy, most of them in the developing world. Reproductive genetic testing in big cities and in private for-profit ventures cater to the socioeconomic elite. Amniocentesis is often misused for fetal sex determination to abort female fetuses in India. Currently, in Cuba virtually every pregnant woman is tested for sickle cell trait and maternal serum alpha-fetoprotein levels between 15 and 20 weeks of gestation. It is predicted that the judicious use of reproductive genetic testing will be possible when health and quality of life issues are addressed properly.

Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests.

PubMed

Baker, Joanne; McCarthy, James; Gatton, Michelle; Kyle, Dennis E; Belizario, Vicente; Luchavez, Jennifer; Bell, David; Cheng, Qin

2005-09-01

Rising costs of antimalarial agents are increasing the demand for accurate diagnosis of malaria. Rapid diagnostic tests (RDTs) offer great potential to improve the diagnosis of malaria, particularly in remote areas. Many RDTs are based on the detection of Plasmodium falciparum histidine-rich protein (PfHRP) 2, but reports from field tests have questioned their sensitivity and reliability. We hypothesize that the variability in the results of PfHRP2-based RDTs is related to the variability in the target antigen. We tested this hypothesis by examining the genetic diversity of PfHRP2, which includes numerous amino acid repeats, in 75 P. falciparum lines and isolates originating from 19 countries and testing a subset of parasites by use of 2 PfHRP2-based RDTs. We observed extensive diversity in PfHRP2 sequences, both within and between countries. Logistic regression analysis indicated that 2 types of repeats were predictive of RDT detection sensitivity (87.5% accuracy), with predictions suggesting that only 84% of P. falciparum parasites in the Asia-Pacific region are likely to be detected at densities < or = 250 parasites/microL. Our data also indicated that PfHRP3 may play a role in the performance of PfHRP2-based RDTs. These findings provide an alternative explanation for the variable sensitivity in field tests of malaria RDTs that is not due to the quality of the RDTs.

Accounting for trait architecture in genomic predictions of US Holstein cattle using a weighted realized relationship matrix.

PubMed

Tiezzi, Francesco; Maltecca, Christian

2015-04-02

Genomic BLUP (GBLUP) can predict breeding values for non-phenotyped individuals based on the identity-by-state genomic relationship matrix (G). The G matrix can be constructed from thousands of markers spread across the genome. The strongest assumption of G and consequently of GBLUP is that all markers contribute equally to the genetic variance of a trait. This assumption is violated for traits that are controlled by a small number of quantitative trait loci (QTL) or individual QTL with large effects. In this paper, we investigate the performance of using a weighted genomic relationship matrix (wG) that takes into consideration the genetic architecture of the trait in order to improve predictive ability for a wide range of traits. Multiple methods were used to calculate weights for several economically relevant traits in US Holstein dairy cattle. Predictive performance was tested by k-means cross-validation. Relaxing the GBLUP assumption of equal marker contribution by increasing the weight that is given to a specific marker in the construction of the trait-specific G resulted in increased predictive performance. The increase was strongest for traits that are controlled by a small number of QTL (e.g. fat and protein percentage). Furthermore, bias in prediction estimates was reduced compared to that resulting from the use of regular G. Even for traits with low heritability and lower general predictive performance (e.g. calving ease traits), weighted G still yielded a gain in accuracy. Genomic relationship matrices weighted by marker realized variance yielded more accurate and less biased predictions for traits regulated by few QTL. Genome-wide association analyses were used to derive marker weights for creating weighted genomic relationship matrices. However, this can be cumbersome and prone to low stability over generations because of erosion of linkage disequilibrium between markers and QTL. Future studies may include other sources of information, such as functional annotation and gene networks, to better exploit the genetic architecture of traits and produce more stable predictions.

Landscape heterogeneity predicts gene flow in a widespread polymorphic bumble bee, Bombus bifarius (Hymentoptera: Apidae).

USDA-ARS?s Scientific Manuscript database

Bombus bifarius is a widespread bumble bee that occurs in montane regions of western North America. This species has several major color polymorphisms, and shows evidence of genetic structuring among regional populations. We test whether this structure is evidence for discrete gene flow barriers tha...

Why Don't Smart Teens Have Sex? A Behavioral Genetic Approach

ERIC Educational Resources Information Center

Harden, Kathryn P.; Mendle, Jane

2011-01-01

Academic achievement and cognitive ability have been shown to predict later age at first sexual intercourse. Using a sample of 536 same-sex twin pairs who were followed longitudinally from adolescence to early adulthood, this study tested whether relations between intelligence, academic achievement, and age at first sex were due to unmeasured…

Gene flow in complex landscapes: Testing multiple hypotheses with causal modeling

Treesearch

Samuel A. Cushman; Kevin S. McKelvey; Jim Hayden; Michael K. Schwartz

2006-01-01

Predicting population-level effects of landscape change depends on identifying factors that influence population connectivity in complex landscapes. However, most putative movement corridors and barriers have not been based on empirical data. In this study, we identify factors that influence connectivity by comparing patterns of genetic similarity among 146 black bears...

Genetically Influenced Change in Sensation Seeking Drives the Rise of Delinquent Behavior during Adolescence

ERIC Educational Resources Information Center

Harden, K. Paige; Quinn, Patrick D.; Tucker-Drob, Elliot M.

2012-01-01

Sensation seeking is associated with an increased propensity for delinquency, and emerging research on personality change suggests that mean levels of sensation seeking increase substantially from childhood to adolescence. The current study tested whether individual differences in the rate of change of sensation seeking predicted within-person…

Genetic benefits of a female mating preference in gray tree frogs are context-dependent.

PubMed

Welch, Allison M

2003-04-01

"Good genes" models of sexual selection predict that male courtship displays can advertise genetic quality and that, by mating with males with extreme displays, females can obtain genetic benefits for their offspring. However, because the relative performance of different genotypes can vary across environments, these genetic benefits may depend on the environmental context; in which case, static mating preferences may not be adaptive. To better understand how selection acts on the preference that female gray tree frogs (Hyla versicolor) express for long advertisement calls, I tested for genetic benefits in two realistic natural environments, by comparing the performance of half-sibling offspring sired by males with long versus short calls. Tadpoles from twelve such maternal half-sibships were raised in enclosures in their natal pond at two densities. In the low-density treatment, offspring of long-call males were larger at metamorphosis than were offspring of short-call males, whereas in the high-density treatment, offspring of males with long calls tended to metamorphose later than offspring of males with short calls. Thus, although the genes indicated by long calls were advantageous under low-density conditions, they were not beneficial under all conditions, suggesting that a static preference for long calls may not be adaptive in all environments. Such a genotype-by-environment interaction in the genetic consequences of mate choice predicts that when the environment is variable, selection may favor plasticity in female preferences or female selectivity among environments to control the conditions experienced by the offspring.

Application of matrix-assisted laser desorption ionization time-of-flight mass spectrometry in the screening of vanA-positive Enterococcus faecium.

PubMed

Wang, Li-jun; Lu, Xin-xin; Wu, Wei; Sui, Wen-jun; Zhang, Gui

2014-01-01

In order to evaluate a rapid matrix-assisted laser desorption ionization-time of flight mass spectrometry (MAIDI-TOF MS) assay in screening vancomycin-resistant Enterococcus faecium, a total of 150 E. faecium clinical strains were studied, including 60 vancomycin-resistant E. faecium (VREF) isolates and 90 vancomycin-susceptible (VSEF) strains. Vancomycin resistance genes were detected by sequencing. E. faecium were identified by MALDI-TOF MS. A genetic algorithm model with ClinProTools software was generated using spectra of 30 VREF isolates and 30 VSEF isolates. Using this model, 90 test isolates were discriminated between VREF and VSEF. The results showed that all sixty VREF isolates carried the vanA gene. The performance of VREF detection by the genetic algorithm model of MALDI-TOF MS compared to the sequencing method was sensitivity = 80%, specificity = 90%, false positive rate =10%, false negative rate =10%, positive predictive value = 80%, negative predictive value= 90%. MALDI-TOF MS can be used as a screening test for discrimination between vanA-positive E. faecium and vanA-negative E. faecium.

Determination of the Spatial Distribution in Hydraulic Conductivity Using Genetic Algorithm Optimization

NASA Astrophysics Data System (ADS)

Aksoy, A.; Lee, J. H.; Kitanidis, P. K.

2016-12-01

Heterogeneity in hydraulic conductivity (K) impacts the transport and fate of contaminants in subsurface as well as design and operation of managed aquifer recharge (MAR) systems. Recently, improvements in computational resources and availability of big data through electrical resistivity tomography (ERT) and remote sensing have provided opportunities to better characterize the subsurface. Yet, there is need to improve prediction and evaluation methods in order to obtain information from field measurements for better field characterization. In this study, genetic algorithm optimization, which has been widely used in optimal aquifer remediation designs, was used to determine the spatial distribution of K. A hypothetical 2 km by 2 km aquifer was considered. A genetic algorithm library, PGAPack, was linked with a fast Fourier transform based random field generator as well as a groundwater flow and contaminant transport simulation model (BIO2D-KE). The objective of the optimization model was to minimize the total squared error between measured and predicted field values. It was assumed measured K values were available through ERT. Performance of genetic algorithm in predicting the distribution of K was tested for different cases. In the first one, it was assumed that observed K values were evaluated using the random field generator only as the forward model. In the second case, as well as K-values obtained through ERT, measured head values were incorporated into evaluation in which BIO2D-KE and random field generator were used as the forward models. Lastly, tracer concentrations were used as additional information in the optimization model. Initial results indicated enhanced performance when random field generator and BIO2D-KE are used in combination in predicting the spatial distribution in K.

Genetic testing for hereditary cancer: effects of alexithymia and coping strategies on variations in anxiety before and after result disclosure.

PubMed

Fantini-Hauwel, Carole; Dauvier, Bruno; Arciszewski, Thomas; Antoine, Pascal; Manouvrier, Sylvie

2011-07-01

This study assessed the impact of the results of genetic testing for hereditary cancer from a multifactorial health psychology perspective, considering that emotional expression plays a key role in psychological adjustment. Measures of dispositional and transactional coping strategies, anxiety and alexithymia were filled out by 77 participants in a longitudinal study design. Statistical analyses were performed using general linear models and partial least squares path modelling, low-constraint methods that are particularly useful in the behavioural sciences. While anxiety levels prior to the result announcement were predictive of the distress experienced by noncarriers, considerable variability was observed for mutation carriers. Some subjects who had lower anxiety levels before the test displayed greater anxiety afterwards, but others seemed to anticipate the distress they would experience with the result that they showed a decrease in anxiety. The mutation carriers behaved as though their adaptive functioning were reshaped by the test result, independent of their disposition and previous emotional state, except in the case of alexithymia. Difficulty expressing emotions prior to genetic testing contributed to a similar difficulty after receiving the result, adding to the latter's emotional impact by promoting emotion-focused coping strategies and increasing distress. © 2011 Taylor & Francis

Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study.

PubMed

Murray, Anna; Bennett, Claire E; Perry, John R B; Weedon, Michael N; Jacobs, Patricia A; Morris, Danielle H; Orr, Nicholas; Schoemaker, Minouk J; Jones, Michael; Ashworth, Alan; Swerdlow, Anthony J

2011-01-01

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.

The statistical analysis of multi-environment data: modeling genotype-by-environment interaction and its genetic basis

PubMed Central

Malosetti, Marcos; Ribaut, Jean-Marcel; van Eeuwijk, Fred A.

2013-01-01

Genotype-by-environment interaction (GEI) is an important phenomenon in plant breeding. This paper presents a series of models for describing, exploring, understanding, and predicting GEI. All models depart from a two-way table of genotype by environment means. First, a series of descriptive and explorative models/approaches are presented: Finlay–Wilkinson model, AMMI model, GGE biplot. All of these approaches have in common that they merely try to group genotypes and environments and do not use other information than the two-way table of means. Next, factorial regression is introduced as an approach to explicitly introduce genotypic and environmental covariates for describing and explaining GEI. Finally, QTL modeling is presented as a natural extension of factorial regression, where marker information is translated into genetic predictors. Tests for regression coefficients corresponding to these genetic predictors are tests for main effect QTL expression and QTL by environment interaction (QEI). QTL models for which QEI depends on environmental covariables form an interesting model class for predicting GEI for new genotypes and new environments. For realistic modeling of genotypic differences across multiple environments, sophisticated mixed models are necessary to allow for heterogeneity of genetic variances and correlations across environments. The use and interpretation of all models is illustrated by an example data set from the CIMMYT maize breeding program, containing environments differing in drought and nitrogen stress. To help readers to carry out the statistical analyses, GenStat® programs, 15th Edition and Discovery® version, are presented as “Appendix.” PMID:23487515

Using probability modelling and genetic parentage assignment to test the role of local mate availability in mating system variation.

PubMed

Blyton, Michaela D J; Banks, Sam C; Peakall, Rod; Lindenmayer, David B

2012-02-01

The formal testing of mating system theories with empirical data is important for evaluating the relative importance of different processes in shaping mating systems in wild populations. Here, we present a generally applicable probability modelling framework to test the role of local mate availability in determining a population's level of genetic monogamy. We provide a significance test for detecting departures in observed mating patterns from model expectations based on mate availability alone, allowing the presence and direction of behavioural effects to be inferred. The assessment of mate availability can be flexible and in this study it was based on population density, sex ratio and spatial arrangement. This approach provides a useful tool for (1) isolating the effect of mate availability in variable mating systems and (2) in combination with genetic parentage analyses, gaining insights into the nature of mating behaviours in elusive species. To illustrate this modelling approach, we have applied it to investigate the variable mating system of the mountain brushtail possum (Trichosurus cunninghami) and compared the model expectations with the outcomes of genetic parentage analysis over an 18-year study. The observed level of monogamy was higher than predicted under the model. Thus, behavioural traits, such as mate guarding or selective mate choice, may increase the population level of monogamy. We show that combining genetic parentage data with probability modelling can facilitate an improved understanding of the complex interactions between behavioural adaptations and demographic dynamics in driving mating system variation. © 2011 Blackwell Publishing Ltd.

Whole genome prediction and heritability of childhood asthma phenotypes.

PubMed

McGeachie, Michael J; Clemmer, George L; Croteau-Chonka, Damien C; Castaldi, Peter J; Cho, Michael H; Sordillo, Joanne E; Lasky-Su, Jessica A; Raby, Benjamin A; Tantisira, Kelan G; Weiss, Scott T

2016-12-01

While whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma-related phenotypes. We applied several WGP methods to a well-phenotyped cohort of 832 children with mild-to-moderate asthma from CAMP. We assessed narrow-sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre- and post-bronchodilator forced expiratory volume in 1 sec (FEV 1 ), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort. We found that longitudinal lung function phenotypes demonstrated significant narrow-sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4-8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts. Longitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP-prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma-related heritable traits.

Parent-child genetic testing for familial hypercholesterolaemia in an Australian context.

PubMed

Pang, Jing; Martin, Andrew C; Bates, Timothy R; Hooper, Amanda J; Bell, Damon A; Burnett, John R; Norman, Richard; Watts, Gerald F

2018-04-06

The aim of this study was to evaluate the clinical outcome of parent-child testing for familial hypercholesterolaemia (FH) employing genetic testing and the likely additional cost of treating each child. Parent-child testing for gene variants causative of FH was carried out according to Australian guidelines. The number of new cases detected, the low-density lipoprotein (LDL)-cholesterol that best predicted a mutation and the proportional reduction in LDL-cholesterol following statin treatment was evaluated. Treatment costs were calculated as the cost per mmol/L reduction in LDL-cholesterol. A total of 126 adult patients, known to have a pathogenic mutation causative of FH, and their children were studied. From 244 children identified, 148 (60.7%) were genetically screened; 84 children were identified as mutative positive (M+) and 64 as mutative negative. Six of the M+ children were already on statin treatment; 40 were subsequently treated with low-dose statins, with LDL-cholesterol falling significantly by 38% (P < 0.001). The estimated cost per mmol/L reduction of LDL-cholesterol of a child receiving statins from ages 10 to 18 years is AU$1361, which can potentially be cost-effective. An LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and specificity of 96.6% for the detection of a mutation. Genetic testing of children of affected parents with FH is an effective means of detecting new cases of FH. Cascade testing can enable early statin therapy with significant reductions in LDL-cholesterol concentration. © 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age

PubMed Central

Morgan, Angharad R.; Thompson, John M.D.; Waldie, Karen E.; Cornforth, Christine M.; Turic, Darko; Sonuga-Barke, Edmund J.S.; Lam, Wen-Jiun; Ferguson, Lynnette R.; Mitchell, Edwin A.

2012-01-01

Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined – that SGA marks pre-existing genetic risk for later problems. PMID:27625810

Genetic Analysis of Milk Yield in First-Lactation Holstein Friesian in Ethiopia: A Lactation Average vs Random Regression Test-Day Model Analysis

PubMed Central

Meseret, S.; Tamir, B.; Gebreyohannes, G.; Lidauer, M.; Negussie, E.

2015-01-01

The development of effective genetic evaluations and selection of sires requires accurate estimates of genetic parameters for all economically important traits in the breeding goal. The main objective of this study was to assess the relative performance of the traditional lactation average model (LAM) against the random regression test-day model (RRM) in the estimation of genetic parameters and prediction of breeding values for Holstein Friesian herds in Ethiopia. The data used consisted of 6,500 test-day (TD) records from 800 first-lactation Holstein Friesian cows that calved between 1997 and 2013. Co-variance components were estimated using the average information restricted maximum likelihood method under single trait animal model. The estimate of heritability for first-lactation milk yield was 0.30 from LAM whilst estimates from the RRM model ranged from 0.17 to 0.29 for the different stages of lactation. Genetic correlations between different TDs in first-lactation Holstein Friesian ranged from 0.37 to 0.99. The observed genetic correlation was less than unity between milk yields at different TDs, which indicated that the assumption of LAM may not be optimal for accurate evaluation of the genetic merit of animals. A close look at estimated breeding values from both models showed that RRM had higher standard deviation compared to LAM indicating that the TD model makes efficient utilization of TD information. Correlations of breeding values between models ranged from 0.90 to 0.96 for different group of sires and cows and marked re-rankings were observed in top sires and cows in moving from the traditional LAM to RRM evaluations. PMID:26194217

Genetic diversity is largely unpredictable but scales with museum occurrences in a species-rich clade of Australian lizards

PubMed Central

Huang, Huateng; Title, Pascal O.; Donnellan, Stephen C.; Holmes, Iris; Rabosky, Daniel L.

2017-01-01

Genetic diversity is a fundamental characteristic of species and is affected by many factors, including mutation rate, population size, life history and demography. To better understand the processes that influence levels of genetic diversity across taxa, we collected genome-wide restriction-associated DNA data from more than 500 individuals spanning 76 nominal species of Australian scincid lizards in the genus Ctenotus. To avoid potential biases associated with variation in taxonomic practice across the group, we used coalescent-based species delimitation to delineate 83 species-level lineages within the genus for downstream analyses. We then used these genetic data to infer levels of within-population genetic diversity. Using a phylogenetically informed approach, we tested whether variation in genetic diversity could be explained by population size, environmental heterogeneity or historical demography. We find that the strongest predictor of genetic diversity is a novel proxy for census population size: the number of vouchered occurrences in museum databases. However, museum occurrences only explain a limited proportion of the variance in genetic diversity, suggesting that genetic diversity might be difficult to predict at shallower phylogenetic scales. PMID:28469025

Genetic diversity is largely unpredictable but scales with museum occurrences in a species-rich clade of Australian lizards.

PubMed

Singhal, Sonal; Huang, Huateng; Title, Pascal O; Donnellan, Stephen C; Holmes, Iris; Rabosky, Daniel L

2017-05-17

Genetic diversity is a fundamental characteristic of species and is affected by many factors, including mutation rate, population size, life history and demography. To better understand the processes that influence levels of genetic diversity across taxa, we collected genome-wide restriction-associated DNA data from more than 500 individuals spanning 76 nominal species of Australian scincid lizards in the genus Ctenotus To avoid potential biases associated with variation in taxonomic practice across the group, we used coalescent-based species delimitation to delineate 83 species-level lineages within the genus for downstream analyses. We then used these genetic data to infer levels of within-population genetic diversity. Using a phylogenetically informed approach, we tested whether variation in genetic diversity could be explained by population size, environmental heterogeneity or historical demography. We find that the strongest predictor of genetic diversity is a novel proxy for census population size: the number of vouchered occurrences in museum databases. However, museum occurrences only explain a limited proportion of the variance in genetic diversity, suggesting that genetic diversity might be difficult to predict at shallower phylogenetic scales. © 2017 The Author(s).

Impact of QTL minor allele frequency on genomic evaluation using real genotype data and simulated phenotypes in Japanese Black cattle.

PubMed

Uemoto, Yoshinobu; Sasaki, Shinji; Kojima, Takatoshi; Sugimoto, Yoshikazu; Watanabe, Toshio

2015-11-19

Genetic variance that is not captured by single nucleotide polymorphisms (SNPs) is due to imperfect linkage disequilibrium (LD) between SNPs and quantitative trait loci (QTLs), and the extent of LD between SNPs and QTLs depends on different minor allele frequencies (MAF) between them. To evaluate the impact of MAF of QTLs on genomic evaluation, we performed a simulation study using real cattle genotype data. In total, 1368 Japanese Black cattle and 592,034 SNPs (Illumina BovineHD BeadChip) were used. We simulated phenotypes using real genotypes under different scenarios, varying the MAF categories, QTL heritability, number of QTLs, and distribution of QTL effect. After generating true breeding values and phenotypes, QTL heritability was estimated and the prediction accuracy of genomic estimated breeding value (GEBV) was assessed under different SNP densities, prediction models, and population size by a reference-test validation design. The extent of LD between SNPs and QTLs in this population was higher in the QTLs with high MAF than in those with low MAF. The effect of MAF of QTLs depended on the genetic architecture, evaluation strategy, and population size in genomic evaluation. In genetic architecture, genomic evaluation was affected by the MAF of QTLs combined with the QTL heritability and the distribution of QTL effect. The number of QTL was not affected on genomic evaluation if the number of QTL was more than 50. In the evaluation strategy, we showed that different SNP densities and prediction models affect the heritability estimation and genomic prediction and that this depends on the MAF of QTLs. In addition, accurate QTL heritability and GEBV were obtained using denser SNP information and the prediction model accounted for the SNPs with low and high MAFs. In population size, a large sample size is needed to increase the accuracy of GEBV. The MAF of QTL had an impact on heritability estimation and prediction accuracy. Most genetic variance can be captured using denser SNPs and the prediction model accounted for MAF, but a large sample size is needed to increase the accuracy of GEBV under all QTL MAF categories.