A Survey of U.S Adults' Opinions about Conduct of a Nationwide Precision Medicine Initiative® Cohort Study of Genes and Environment.

OBJECTIVES: A survey of a population-based sample of U.S adults was conducted to measure their attitudes about, and inform the design of the Precision Medicine Initiative's planned national cohort study. METHODS: An online survey was conducted by GfK between May and June of 2015. The influence of different consent models on willingness to share data was examined by randomizing participants to one of eight consent scenarios. RESULTS: Of 4,777 people invited to take the survey, 2,706 responded and 2,601 (54% response rate) provided valid responses. Most respondents (79%) supported the proposed study, and 54% said they would definitely or probably participate if asked. Support for and willingness to participate in the study varied little among demographic groups; younger respondents, LGBT respondents, and those with more years of education were significantly more likely to take part if asked. The most important study incentive that the survey asked about was learning about one's own health information. Willingness to share data and samples under broad, study-by-study, menu and dynamic consent models was similar when a statement about transparency was included in the consent scenarios. Respondents were generally interested in taking part in several governance functions of the cohort study. CONCLUSIONS: A large majority of the U.S. adults who responded to the survey supported a large national cohort study. Levels of support for the study and willingness to participate were both consistent across most demographic groups. The opportunity to learn health information about one's self from the study appears to be a strong motivation to participate.

Impact of Psychiatric Information on Potential Jurors in Evaluating High-Functioning Autism Spectrum Disorder (hfASD).

During a trial involving an offender with a mental disorder, jurors are often required to evaluate information on the disorder and its characteristics. This evaluation relies on how jurors understand and synthesize psychiatric and other evidence on the disorder and this information's impact on the case, an offender's culpability, and the rendered verdict. The importance of this evaluation is further highlighted when jurors are faced with evaluating a disorder that may be associated with criminal actions of diagnosed offenders, such as high-functioning autism spectrum disorder (hfASD). We designed a three-part survey to assess potential jurors' attitudes concerning an offender's diagnosis with hfASD in terms of perceptions and decisions surrounding legal and moral responsibility, personal characteristics of the offender, the introduction of psychiatric and genetic information, and the condition's influence on the facts of the case. A sample of 623 jury-eligible U.S. adults completed the survey. We found the majority of participants were influenced by the information provided on hfASD. Most respondents indicated that hfASD diagnosis should generally not affect the legal responsibility of an offender, but many reported the disorder as a mitigating factor when evaluating moral responsibility and legal consequences for criminal actions. Respondents reported favorable and sympathetic perceptions of individuals with autism and associated characteristics but were unsure, even after the presentation of psychiatric information on hfASD, if these disorders should be classified as "mental illness." Further, the majority reported their views were in some way influenced by the fact that hfASD has potential genetic origins.

Novel MPDZ/MUPP1 transgenic and knockdown models confirm Mpdz's role in ethanol withdrawal and support its role in voluntary ethanol consumption.

Association studies implicate multiple PDZ domain protein (MPDZ/MUPP1) sequence and/or expression in risk for alcoholism in humans and ethanol withdrawal (EW) in mice, but confirmation has been hindered by the dearth of targeted genetic models. We report the creation of transgenic (MPDZ-TG) and knockout heterozygote (Mpdz(+/-) ) mice, with increased (2.9-fold) and decreased (53%) target expression, respectively. Both models differ in EW compared with wild-type littermates (P ≤ 0.03), providing compelling evidence for an inverse relationship between Mpdz expression and EW severity. Additionally, ethanol consumption is reduced up to 18% (P = 0.006) in Mpdz(+/-) , providing the first evidence implicating Mpdz in ethanol self-administration.

Genomics in the clinic: ethical and policy challenges in clinical next-generation sequencing programs at early adopter USA institutions.

Next-generation sequencing (NGS) technologies are poised to revolutionize clinical diagnosis and treatment, but raise significant ethical and policy challenges. This review examines NGS program challenges through a synthesis of published literature, website and conference presentation content, and interviews at early-adopting institutions in the USA. Institutions are proactively addressing policy challenges related to the management and technical aspects of program development. However, ethical challenges related to patient-related aspects have not been fully addressed. These complex challenges present opportunities to develop comprehensive and standardized regulations across programs. Understanding the strengths, weaknesses and current practices of evolving NGS program approaches are important considerations for institutions developing NGS services, policymakers regulating or funding NGS programs and physicians and patients considering NGS services.

Focusing on Cause or Cure?: Priorities and Stakeholder Presence in Childhood Psychiatry Research.

BACKGROUND: Biomedical research is influenced by many factors, including the involvement of stakeholder groups invested in research outcomes. Stakeholder involvement in research efforts raise questions of justice as their specific interests and motivations play a role in directing research resources that ultimately produce knowledge shaping how different conditions (and affected individuals) are understood and treated by society. This issue is highly relevant to child psychiatry research where diagnostic criteria and treatment strategies are often controversial. Biological similarities and stakeholder differences between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) provide an opportunity to explore this issue by comparing research foci and stakeholder involvement in these conditions. METHODS: A subset of ADHD and ASD research articles published between 1970-2010 were randomly selected from the PubMed database and coded for research focus, funding source(s), and author-reported conflicts of interest (COIs). Chi-square analyses were performed to identify differences between and within ADHD and ASD research across time. RESULTS: The proportion of ADHD research dedicated to basic, description, and treatment research was roughly similar and remained stable over time, while ASD research showed a significant increase in basic research over the past decade. Government was the primary research funder for both conditions, but for-profit funders were a notable presence in ADHD research, while joint-funding efforts between non-profit and government funders were a notable presence in ASD research. Lastly, COIs were noted more frequently in ADHD than in ASD research. CONCLUSIONS: Our study shows significant differences in research foci and funding sources between the conditions, and identifies the specific involvement of for-profit and non-profit groups in ADHD and ASD, respectively. Our findings highlight the relationship between stakeholders outside the research community and research trajectories and suggest that examinations of these relationships must be included in broader considerations of biomedical research ethics.

Quality of communication in interpreted versus noninterpreted PICU family meetings.

OBJECTIVES: To describe the quality of physician-family communication during interpreted and noninterpreted family meetings in the PICU. DESIGN: Prospective, exploratory, descriptive observational study of noninterpreted English family meetings and interpreted Spanish family meetings in the pediatric intensive care setting. SETTING: A single, university-based, tertiary children's hospital. SUBJECTS: Participants in PICU family meetings, including medical staff, family members, ancillary staff, and interpreters. INTERVENTIONS: Thirty family meetings (21 English and nine Spanish) were audio-recorded, transcribed, de-identified, and analyzed using the qualitative method of directed content analysis. MEASUREMENTS AND MAIN RESULTS: Quality of communication was analyzed in three ways: 1) presence of elements of shared decision-making, 2) balance between physician and family speech, and 3) complexity of physician speech. Of the 11 elements of shared decision-making, only four occurred in more than half of English meetings, and only three occurred in more than half of Spanish meetings. Physicians spoke for a mean of 20.7 minutes, while families spoke for 9.3 minutes during English meetings. During Spanish meetings, physicians spoke for a mean of 14.9 minutes versus just 3.7 minutes of family speech. Physician speech complexity received a mean grade level score of 8.2 in English meetings compared to 7.2 in Spanish meetings. CONCLUSIONS: The quality of physician-family communication during PICU family meetings is poor overall. Interpreted meetings had poorer communication quality as evidenced by fewer elements of shared decision-making and greater imbalance between physician and family speech. However, physician speech may be less complex during interpreted meetings. Our data suggest that physicians can improve communication in both interpreted and noninterpreted family meetings by increasing the use of elements of shared decision-making, improving the balance between physician and family speech, and decreasing the complexity of physician speech.

Discovering genes involved in alcohol dependence and other alcohol responses: role of animal models.

The genetic determinants of alcoholism still are largely unknown, hindering effective treatment and prevention. Systematic approaches to gene discovery are critical if novel genes and mechanisms involved in alcohol dependence are to be identified. Although no animal model can duplicate all aspects of alcoholism in humans, robust animal models for specific alcohol-related traits, including physiological alcohol dependence and associated withdrawal, have been invaluable resources. Using a variety of genetic animal models, the identification of regions of chromosomal DNA that contain a gene or genes which affect a complex phenotype (i.e., quantitative trait loci [QTLs]) has allowed unbiased searches for candidate genes. Several QTLs with large effects on alcohol withdrawal severity in mice have been detected, and fine mapping of these QTLs has placed them in small intervals on mouse chromosomes 1 and 4 (which correspond to certain regions on human chromosomes 1 and 9). Subsequent work led to the identification of underlying quantitative trait genes (QTGs) (e.g., Mpdz) and high-quality QTG candidates (e.g., Kcnj9 and genes involved in mitochondrial respiration and oxidative stress) and their plausible mechanisms of action. Human association studies provide supporting evidence that these QTLs and QTGs may be directly relevant to alcohol risk factors in clinical populations.

Identifying quantitative trait loci (QTLs) and genes (QTGs) for alcohol-related phenotypes in mice.

Alcoholism is a complex clinical disorder with genetic and environmental contributions. Although no animal model duplicates alcoholism, models for specific factors, such as the withdrawal syndrome, are useful to identify potential genetic determinants of liability in humans. Murine models have been invaluable to identify quantitative trait loci (QTLs) that influence a variety of alcohol responses. However, the QTL regions are typically large, at least initially, and contain numerous genes, making identification of the causal quantitative trait gene(s) (QTGs) challenging. Here, we present QTG identification strategies currently used in the field of alcohol genetics and discuss relevance to alcoholic human populations.

Mapping a barbiturate withdrawal locus to a 0.44 Mb interval and analysis of a novel null mutant identify a role for Kcnj9 (GIRK3) in withdrawal from pentobarbital, zolpidem, and ethanol.

Here, we map a quantitative trait locus (QTL) with a large effect on predisposition to barbiturate (pentobarbital) withdrawal to a 0.44 Mb interval of mouse chromosome 1 syntenic with human 1q23.2. We report a detailed analysis of the genes within this interval and show that it contains 15 known and predicted genes, 12 of which demonstrate validated genotype-dependent transcript expression and/or nonsynonymous coding sequence variation that may underlie the influence of the QTL on withdrawal. These candidates are involved in diverse cellular functions including intracellular trafficking, potassium conductance and spatial buffering, and multimolecular complex dynamics, and indicate both established and novel aspects of neurobiological response to sedative-hypnotics. This work represents a substantial advancement toward identification of the gene(s) that underlie the phenotypic effects of the QTL. We identify Kcnj9 as a particularly promising candidate and report the development of a Kcnj9-null mutant model that exhibits significantly less severe withdrawal from pentobarbital as well as other sedative-hypnotics (zolpidem and ethanol) versus wild-type littermates. Reduced expression of Kcnj9, which encodes GIRK3 (Kir3.3), is associated with less severe sedative-hypnotic withdrawal. A multitude of QTLs for a variety of complex traits, including diverse responses to sedative-hypnotics, have been detected on distal chromosome 1 in mice, and as many as four QTLs on human chromosome 1q have been implicated in human studies of alcohol dependence. Thus, our results will be primary to additional efforts to identify genes involved in a wide variety of behavioral responses to sedative-hypnotics and may directly facilitate progress in human genetics.

5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice.

Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT2C and/or GABAB receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is >99% from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT2C receptor antagonist (SB242084) or a GABAB receptor agonist (baclofen), but not a GABAA receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT2C and/or GABAB receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.

Interval-specific congenic animals for high-resolution quantitative trait loci mapping.

Behavioral phenotypes (e.g., drug responses and withdrawal) are typically quantitative traits-characteristics that differ along a spectrum in the extent to which an individual possesses that characteristic. Such traits are determined by multiple genes, as well as by environmental factors and interactions among genes and environmental factors. The chromosomal regions containing these genes are commonly referred to as quantitative trait loci (QTLs). As described in the preceding article by Hitzemann and colleagues (pp. 270- 271), researchers have developed a variety of strategies to attain greater precision when mapping QTLs (Darvasi 1998; Talbot et al. 1999), which is necessary for unbiased genomewide approaches such as QTL mapping to be successful in ultimately identifying which gene(s) underlies a QTL's phenotypic influence. Among these, some approaches are clearly superior for fine mapping QTLs associated with behavioral traits. One such strategy employs specially bred animals known as interval-specific congenics (ISCs) (sometimes called small donor segment congenics). This article introduces the use of these animals in mapping QTLs associated with certain responses to alcohol.