Informed consent and the misattributed paternity problem in genetic counseling

When misattributed paternity is discovered in the course of genetic testing, a genetic counselor is presented with a dilemma concerning whether to reveal this information to the clients. She is committed to treating the clients equally and enabling informed decision making, but disclosing the information may carry consequences for the woman that the counselor cannot judge in advance. A frequent suggestion aimed at avoiding this problem is to include the risk of discovering nonpaternity in the informed consent process for counseling. In this paper I argue that such a move does not resolve the problem, because the conflict hinges on the interpretation of equality on which the counselor operates. Given the principles of genetic counseling, neither construal of equality yields a satisfactory solution to the conflict. In fact, I conclude that including nonpaternity in informed consent is not endorsed by either view, and we are still left with the question of what to do should nonpaternity be discovered. I suggest a compromise position concerning disclosure, involving revealing relevant genetic information but withholding nonpaternity when possible.     

Accepting Adoption’s Uncertainty: The Limited Ethics of Pre-Adoption Genetic Testing

An increasing number of children are adopted in the United States from countries where both medical care and environmental conditions are extremely poor. In response to worries about the accuracy of medical histories, prospective adoptive parents increasingly request genetic testing of children prior to adoption. Though a general consensus on the ethics of pre-adoption genetic testing (PAGT) argues against permitting genetic testing on children available for adoption that is not also permitted for children in general, a view gaining traction argues for expanding the tests permitted. The reasoning behind this view is that the State has a duty to provide a child with parents who are the best “match,” and thus all information that advances this end should be obtained. While the matching argument aims to promote the best interests of children, I show how it rests on the claim that what is in the best interests of children available for adoption is for prospective adoptive parents to have their genetic preferences satisfied such that the “genetics” of the children they end up adopting accurately reflects those preferences. Instead of protecting a vulnerable population, I conclude, PAGT contributes to the risks of harm such children face as it encourages people with strong genetic preferences to adopt children whose genetic backgrounds will always be uncertain.     

The new biochemistry: in praise of alternate curricula

The problem of what to include or exclude in designing a modern biochemistry course is becoming increasingly difficult to resolve. In this article, I suggest that the focus on which topics are to be covered is misplaced. Since factual information is rapidly forgotten, whereas skills can be retained, students would be better served if we designed our courses around those skill sets we desire our students to learn.     

Owning Genetic Information and Gene Enhancement Techniques: Why Privacy and Property Rights May Undermine Social Control of the Human Genome

In this article I argue that the proper subjects of intangible property claims include medical records, genetic profiles, and gene enhancement techniques. Coupled with a right to privacy these intangible property rights allow individuals a zone of control that will, in most cases, justifiably exclude governmental or societal invasions into private domains. I argue that the threshold for overriding privacy rights and intangible property rights is higher, in relation to genetic enhancement techniques and sensitive personal information, than is commonly suggested. Once the bar is raised, so-to-speak, the burden of overriding it is formidable. Thus many policy decisions that have been recently proposed or enacted – citywide audio and video surveillance, law enforcement DNA sweeps, genetic profiling, national bans on genetic testing and enhancement of humans, to name a few – will have to be backed by very strong arguments.     

Genetic study of plasmid integration into yeast chromosomes. III. Selection for a phenotype of Saccharomyces cerevisiae (Meyen ex Hansen) clones which lost the 2-micron DNA and their genetic testing

We used the coloured adeI (cir+) haploid strain containing an episomal plasmid integrated into the chromosome I for visual detection and genetic testing of Saccharomyces cerevisiae clones having lost 2 microns DNA. During incubation, colonies of this strain were covered with numerous papillae of the same genotype. Stable clones which did not generate such papillae were isolated. Hybrids of these clones with (cir0) partner were not shown to exhibit destabilization of the chimeric chromosome. The stable clones isolated proved to lack 2 microns DNA, as shown by colony hybridization technique. We conclude therefore that the loss of the cryptic yeast plasmid may be phenotypically detected.     

Informed Consent in Direct‐to‐Consumer Personal Genome Testing: The Outline of A Model between Specific and Generic Consent

Broad genome‐wide testing is increasingly finding its way to the public through the online direct‐to‐consumer marketing of so‐called personal genome tests. Personal genome tests estimate genetic susceptibilities to multiple diseases and other phenotypic traits simultaneously. Providers commonly make use of Terms of Service agreements rather than informed consent procedures. However, to protect consumers from the potential physical, psychological and social harms associated with personal genome testing and to promote autonomous decision‐making with regard to the testing offer, we argue that current practices of information provision are insufficient and that there is a place – and a need – for informed consent in personal genome testing, also when it is offered commercially. The increasing quantity, complexity and diversity of most testing offers, however, pose challenges for information provision and informed consent. Both specific and generic models for informed consent fail to meet its moral aims when applied to personal genome testing. Consumers should be enabled to know the limitations, risks and implications of personal genome testing and should be given control over the genetic information they do or do not wish to obtain. We present the outline of a new model for informed consent which can meet both the norm of providing sufficient information and the norm of providing understandable information. The model can be used for personal genome testing, but will also be applicable to other, future forms of broad genetic testing or screening in commercial and clinical settings.     

Coverage of genetic technologies under national health reform.

This article examines the extent to which the technologies expected to emerge from genetic research are likely to be covered under Government-mandated health insurance programs such as those being proposed by advocates of national health reform. Genetic technologies are divided into three broad categories; genetic information services, including screening, testing, and counseling; experimental technologies; and gene therapy. This article concludes that coverage of these technologies under national health reform is uncertain. The basic benefits packages provided for in the major health reform plans are likely to provide partial coverage of experimental technologies; relatively broad coverage of information services; and varying coverage of gene therapies, on the basis of an evaluation of their costs, benefits, and the degree to which they raise objections on political and religious grounds. Genetic services that are not included in the basic benefits package will be available only to those who can purchase supplemental insurance or to those who can purchase the services with personal funds. The resulting multitiered system of access to genetic services raises serious questions of fairness.     

Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes

Studies have argued that genetic testing will provide limited information for predicting the probability of common diseases, because of the incomplete penetrance of genotypes and the low magnitude of associated risks for the general population. Such studies, however, have usually examined the effect of one gene at time. We argue that disease prediction for common multifactorial diseases is greatly improved by considering multiple predisposing genetic and environmental factors concurrently, provided that the model correctly reflects the underlying disease etiology. We show how likelihood ratios can be used to combine information from several genetic tests to compute the probability of developing a multifactorial disease. To show how concurrent use of multiple genetic tests improves the prediction of a multifactorial disease, we compute likelihood ratios by logistic regression with simulated case-control data for a hypothetical disease influenced by multiple genetic and environmental risk factors. As a practical example, we also apply this approach to venous thrombosis, a multifactorial disease influenced by multiple genetic and nongenetic risk factors. Under reasonable conditions, the concurrent use of multiple genetic tests markedly improves prediction of disease. For example, the concurrent use of a panel of three genetic tests (factor V Leiden, prothrombin variant G20210A, and protein C deficiency) increases the positive predictive value of testing for venous thrombosis at least eightfold. Multiplex genetic testing has the potential to improve the clinical validity of predictive testing for common multifactorial diseases.     

The genetics of muscle atrophy and growth: the impact and implications of polymorphisms in animals and humans

Much of the vast diversity we see in animals and people is governed by genetic loci that have quantitative effects of phenotype (quantitative trait loci; QTLs). Here we review the current knowledge of the genetics of atrophy and hypertrophy in both animal husbandry (meat quantity and quality), and humans (muscle size and performance). The selective breeding of animals for meat has apparently led to a few genetic loci with strong effects, with different loci in different animals. In humans, muscle quantitative trait loci (QTLs) appear to be more complex, with few "major" loci identified to date, although this is likely to change in the near future. We describe how the same phenotypic traits we see as positive, greater lean muscle mass in cattle or a better exercise results in humans, can also have negative "side effects" given specific environmental challenges. We also discuss the strength and limitations of single nucleotide polymorphisms (SNP) association studies; what the reader should look for and expect in a published study. Lastly we discuss the ethical and societal implications of this genetic information. As more and more research into the genetic loci that dictate phenotypic traits become available, the ethical implications of testing for these loci become increasingly important. As a society, most accept testing for genetic diseases or susceptibility, but do we as easily accept testing to determine one's athletic potential to be an Olympic endurance runner, or quarterback on the high school football team.     

An entropy-based approach for testing genetic epistasis underlying complex diseases

The genetic basis of complex diseases is expected to be highly heterogeneous, with complex interactions among multiple disease loci and environment factors. Due to the multi-dimensional property of interactions among large number of genetic loci, efficient statistical approach has not been well developed to handle the high-order epistatic complexity. In this article, we introduce a new approach for testing genetic epistasis in multiple loci using an entropy-based statistic for a case-only design. The entropy-based statistic asymptotically follows a χ² distribution. Computer simulations show that the entropy-based approach has better control of type I error and higher power compared to the standard χ² test. Motivated by a schizophrenia data set, we propose a method for measuring and testing the relative entropy of a clinical phenotype, through which one can test the contribution or interaction of multiple disease loci to a clinical phenotype. A sequential forward selection procedure is proposed to construct a genetic interaction network which is illustrated through a tree-based diagram. The network information clearly shows the relative importance of a set of genetic loci on a clinical phenotype. To show the utility of the new entropy-based approach, it is applied to analyze two real data sets, a schizophrenia data set and a published malaria data set. Our approach provides a fast and testable framework for genetic epistasis study in a case-only design.     

Parental attitudes toward genetic testing for pediatric deafness

Recent molecular genetic advances have resulted in genetic testing becoming an option for deaf individuals and their families. However, there is little information about the interest in such testing. To investigate this issue, parents with normal hearing who have one or more deaf children were surveyed about their attitudes toward diagnostic, carrier, and prenatal genetic testing for deafness. This population was chosen because it represents the majority of individuals who are encountered in clinical practice, given that 90%-95% of deaf individuals are born to persons with normal hearing. Of 328 surveys distributed, 96 were completed and returned. Of the respondents, 96% recorded a positive attitude toward genetic testing for deafness, including prenatal testing, although none would use this information to terminate an affected pregnancy. All respondents had a poor understanding of genetics, with 98% both incorrectly estimating the recurrence risk of deafness and misunderstanding the concept of inheritance. Notably, these findings were similar in the group who had had genetic testing for their children and in the group who had not, suggesting either that the parents who received genetic testing did not receive genetic counseling or that the counseling was not effective. On the basis of these results, it was concluded that this population is interested in the use of genetic testing and that testing should not be done without first providing formal genetic counseling. Appropriate counseling can help parents to understand the risks, benefits, and limitations of genetic testing.     

Empowering international canine inherited disorder management

The mapping of the canine genome and the study of canine breed genomic architecture has revolutionized the discovery of genetic tests for inherited disorders in dogs. As the genetics underlying complex disorders are revealed, canine breeders and their registering organisations will be required to understand genetics in a much more sophisticated way. To facilitate the management of genetic disorders in the era of new complex information, we consider how best to apply the results of new research and analytical techniques to benefit the wider canine breeding community with the aims of improving canine health and maintaining benevolent genetic diversity. If this is not done, there is a serious risk that expensive and valuable genetic research will remain unused or be misused to the detriment of breeds. In this review, we make a case for the formation of an international organisation that will exist as a central repository for breed-based genetic analysis and information sharing. This organisation ("Inter-Dog") could be modelled on a similar organisation that is monitoring genetic improvement of dairy cattle. The formation of such an organisation will require the collaboration of international kennel management organisations, researchers, and agencies offering genetic testing services.     

Opinion: predictive testing for Huntington disease in childhood: challenges and implications.

Predictive testing for HD strongly highlights the need for autonomy and the need for each individual to decide about his or her willingness-or unwillingness-to obtain genetic information predictive of the future outcome. In respect of this principle, testing for minors should not be offered at the request of a third party, and prenatal testing which would result in the birth of a child at increased risk for HD should, where possible, be avoided. If we accede to the wishes of the parents for their children to be tested, we will have broken the primary principles of confidentiality, privacy, and individual justice that are owed to those children. This could be the thin edge of a wedge which could result in adoption agencies, educational institutions, insurance companies, and other third parties demanding genetic testing for another individual. Despite years of careful planning, predictive testing for HD is turning out to be more complex and challenging than ever expected. We need a great deal of care and concern in developing our response to this challenge. Careful long-term assessment and documentation of the impact of such testing is needed, so that the appropriate guidelines can be developed, guidelines which both protect families with HD and at the same time give individuals the opportunity to participate in predictive testing programs.     

Testing Hardy-Weinberg proportions in a frequency-matched case-control genetic association study

In case-control genetic association studies, cases are subjects with the disease and controls are subjects without the disease. At the time of case-control data collection, information about secondary phenotypes is also collected. In addition to studies of primary diseases, there has been some interest in studying genetic variants associated with secondary phenotypes. In genetic association studies, the deviation from Hardy-Weinberg proportion (HWP) of each genetic marker is assessed as an initial quality check to identify questionable genotypes. Generally, HWP tests are performed based on the controls for the primary disease or secondary phenotype. However, when the disease or phenotype of interest is common, the controls do not represent the general population. Therefore, using only controls for testing HWP can result in a highly inflated type I error rate for the disease- and/or phenotype-associated variants. Recently, two approaches, the likelihood ratio test (LRT) approach and the mixture HWP (mHWP) exact test were proposed for testing HWP in samples from case-control studies. Here, we show that these two approaches result in inflated type I error rates and could lead to the removal from further analysis of potential causal genetic variants associated with the primary disease and/or secondary phenotype when the study of primary disease is frequency-matched on the secondary phenotype. Therefore, we proposed alternative approaches, which extend the LRT and mHWP approaches, for assessing HWP that account for frequency matching. The goal was to maintain more (possible causative) single-nucleotide polymorphisms in the sample for further analysis. Our simulation results showed that both extended approaches could control type I error probabilities. We also applied the proposed approaches to test HWP for SNPs from a genome-wide association study of lung cancer that was frequency-matched on smoking status and found that the proposed approaches can keep more genetic variants for association studies.     

The need for anonymous genetic counseling and testing.

Concerns are mounting about the risks of genetic discrimination resulting from the release of predictive and presymptomatic genetic test results to employers, insurers, and others. The ability to keep this information confidential is questionable, particularly in view of the expansion of electronic medical databases. One solution is to afford individuals access to anonymous genetic counseling and testing. Probands would be identified only by a code that would not reveal personal information, and test results would be stored, retrieved, and released solely on the basis of this code. The experience with anonymous HIV testing, while not completely analogous, suggests that such an approach would be both practical and effective.     

DNA sampling and banking in clinical genetics and genetic research

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 US 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.     

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

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.     

Genetic structure of a morphological species within the amoeba genus Korotnevella (Amoebozoa: Discosea), revealed by the analysis of two genes

Amoebae of the genus Korotnevella are covered with scales, the structure of which is believed to be species–specific and allows distinguishing species reliably at the morphological level. We studied members of this genus in order to assess the genetic structure of the local populations of amoebae. For the present study we isolated nine freshwater strains of Korotnevella, belonging to three species, from two locations in North-Western Russia. In order to obtain data on the population structure of these amoebae, we identified all isolates based on the light-microscopic morphology and scale structure and investigated both inter-strain and intra-strain polymorphism of Cox I and 18S rRNA genes. Results show that both genes provide congruent patterns of population structure. The Cox I gene appears to be more reliable DNA barcode while the 18S rRNA gene shows an interesting pattern of polymorphism, which may represent phylotypes of amoebae. Local population of amoebae in every studied species consists of a number of genetic lineages (phylotypes), some shared between the populations while others are unique to a local habitat.     

下一代半导体测序技术在遗传性心肌病分子诊断中的应用

遗传性心肌病(Inherited cardiomyopathy, ICM)是一种常见的遗传性心脏疾病,主要由基因突变所致,是青少年和年轻运动员猝死的最主要原因之一。到目前为止,已经发现约100个基因和其致病有关,这些基因相关的变异位点具有不同的致病机制。随着临床遗传检测在遗传疾病诊断中的应用,对遗传性心肌病的分子遗传学特性及其致病机制进行深入了解,是对该病遗传诊断的关键。下一代半导体测序仪在2010年底由美国Life Technologies公司发布,其以布满微孔的高密度半导体芯片为测序基础,具有快速、经济、灵敏性好、准确率高等特点,已经应用于遗传疾病的突变筛查。文章主要对遗传性心肌病的分子遗传学特性和下一代半导体测序技术在遗传性心肌病遗传检测中的应用以及面临的挑战进行了概括总结,有助于遗传性心肌病的诊断、预防和治疗。     

Allowing for missing parents in genetic studies of case-parent triads

In earlier work, my colleagues and I described a log-linear model for genetic data from triads composed of affected probands and their parents. This model allows detection of and discrimination between effects of an inherited haplotype versus effects of the maternal haplotype, which presumably would be mediated by prenatal factors. Like the transmission disequilibrium test (TDT), the likelihood-ratio test (LRT) based on this model is not sensitive to associations that are due to genetic admixture. When used as a method for testing for linkage disequilibrium, the LRT can be regarded as an alternative to the TDT. When one or both parents are missing, the resulting incomplete triad must be discarded to ensure validity of the TDT, thereby sacrificing information. By contrast, when the problem is set in a likelihood framework, the expectation-maximization algorithm allows the incomplete triads to contribute their information to the LRT without invalidation of the analysis. Simulations demonstrate that much of the lost statistical power can be recaptured by means of this missing-data technique. In fact, power is reasonably good even when no triad is complete-for example, when a study is designed to include only mothers of cases. Information from siblings also can be incorporated to further improve the statistical power when genetic data from parents or probands are missing.