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Despite the fact that direct-to-consumer (DTC) genetic ancestry testing (GAT) has been available for two decades, there is a lack of evidence-based guidance for clinicians who may work with patients who raise the topic of DTC-GAT. Although DTC-GAT accounts for the majority of the DTC genetic testing marketplace, it has received less attention than health-related testing from scientific and clinical communities. Importantly, however, from our personal experience, patients have been raising the topic of DTC-GAT in clinical encounters, including psychotherapy sessions. In this viewpoint, we present two cases of patients seen by two of the authors to raise awareness of this issue. We describe the implications of DTC-GAT for patients and clinicians, offer recommendations, and suggest future directions.

Racist systems, policies, and institutions subvert the quality of life for minoritized individuals and groups, across all indicators, from education and employment, to health, to community safety. Reforms to address systemic racism may be accelerated with greater support from allies who identify with the dominant groups that derive advantage from such systems. Although enhancing empathy and compassion for impacted individuals and groups may foster greater allyship with and support of minoritized communities, little work to date has assessed the relationships among compassion, empathy, and allyship. After reviewing current work in the area, this perspective offers insights into the utility and specific components of a compassion-based framework that can be used to combat racism, using findings from a survey study in which we investigated the relationship between validated psychometric measures of compassion and allyship with minoritized communities. Several subdomains of compassion, as measured among individuals identifying as non-Black, correlate significantly with levels of felt allyship with Black or African American communities. These findings inform recommendations for compassion-focused research, including development and testing of interventions to promote allyship, advocacy, and solidarity with minoritized groups, and support efforts to undo longstanding structural racisms that have patterned inequality in the United States.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic led to the onset and exacerbation of mental health problems, such as stress, anxiety, and depression; yet stay-at-home-orders affected individuals' ability to make use of social support as a coping skill in managing distress. We aimed to evaluate how social support (emotional and instrumental) and biological sex were associated with stress, anxiety, and depression early in the COVID-19 pandemic.MethodsParticipants (n = 7256) had an average age of 50.13 years (SD = 16.75) and 51.6% were male. Using a cross-sequential design, seven cohorts of individuals completed baseline (T1) and one-month follow-up (T2) questionnaires online from March to July of 2020. We used a series of hierarchical regressions to identify types of social support (Brief-COPE, T1) associated with stress (Perceived Stress Scale-10, T1 and T2), anxiety and depression (Patient Health Questionnaire-4, T2).ResultsGreater emotional support was associated with less perceived stress, anxiety and depression (all ps

Broad health data sharing raises myriad ethical issues related to data protection and privacy. These issues are of particular relevance to Native Americans, who reserve distinct individual and collective rights to control data about their communities. We sought to gather input from tribal community leaders on how best to understand health data privacy and sharing preferences in this population. We conducted a workshop with 14 tribal leaders connected to the Strong Heart Study to codesign a research study to assess preferences concerning health data privacy for biomedical research. Workshop participants provided specific recommendations regarding who should be consulted, what questions should be posed, and what methods should be used, underscoring the importance of relationship-building between researchers and tribal communities. Biomedical researchers and informaticians who collect and analyze health information from Native communities have a unique responsibility to safeguard these data in ways that align to the preferences of specific communities.

Background and objectivesSuccessful clinical integration of genomic sequencing (GS) requires evidence of its utility. While GS potentially has benefits (utilities) or harms (disutilities) across multiple domains of life for both patients and their families, there is as yet no empirically informed conceptual model of these effects. Our objective was to develop an empirically informed conceptual model of perceived utility of GS that captures utilities and disutilities for patients and their families across diverse backgrounds.MethodsWe took a patient-centered approach, in which we began with a review of existing literature followed by collection of primary interview data. We conducted semi-structured interviews to explore types of utility in a clinically and sociopolitically diverse sample of 60 adults from seven Clinical Sequencing Evidence-Generating Research (CSER) consortium projects. Interviewees had either personally received, or were parents of a child who had received, GS results. Qualitative data were analyzed using thematic analysis. Findings from interviews were integrated with existing literature on clinical and personal utility to form the basis of an initial conceptual model that was refined based on expert review and feedback.ResultsFive key utility types that have been previously identified in qualitative literature held up as primary domains of utility and disutility in our diverse sample. Interview data were used to specify and organize subdomains of an initial conceptual model. After expert refinement, the five primary domains included in the final model are clinical, emotional, behavioral, cognitive, and social, and several subdomains are specified within each.ConclusionWe present an empirically informed conceptual model of perceived utility of GS. This model can be used to guide development of instruments for patient-centered outcome measurement that capture the range of relevant utilities and disutilities and inform clinical implementation of GS.

Compassion in interactions between physicians and patients can have a therapeutic effect independent of the technical medical treatment provided. However, training physicians to effectively communicate compassion is challenging. This study explores how medical students experienced training focused on interacting with patients by examining students' reports of particularly memorable lessons. Six focus groups were conducted with medical students (total n = 48) in their fourth year of training. We report on responses from students to the question, "What was the most memorable lesson you have learned about interacting with patients?" Students discussed lessons aimed at patient-centered physical navigation, interpersonal navigation, and perspective taking. Concerns were raised that navigation techniques felt inauthentic and that perspective taking was too time consuming to be sustainable in actual practice. While perspective-taking exercises should motivate medical students to treat every patient with dignity by demonstrating the complexity of others' lives, if students assume that full understanding is a prerequisite to delivery of compassionate care, they may dismiss explicit techniques of patient-centered care as inauthentic and perceive compassion and efficiency as mutually exclusive.

This investigation examined how dispositional compassion and empathy were associated with prosocial behaviors and attitudes in the SARS-CoV-2 pandemic. Every two weeks from March 22 to June 15, 2020, we fielded a survey to a new cohort of adults in the U.S. Compassion related to whether one stayed home to protect others, more hours spent staying home and distancing from others, and more frequent mask wearing in public, in the past two weeks. Compassion also related to greater perceived ability to help others who were negatively affected. Empathy related to more endorsement of understanding others' fear of COVID-19, and less endorsement of the view that others were overreacting to COVID-19. There was an interaction between empathy and political ideology, suggesting that empathy may matter for understanding others' fear among those with more conservative-leaning beliefs. Empathy also related to greater understanding that sheltering-in-place helps prevent the spread of COVID-19. Findings suggest that messaging and interventions to increase compassion and empathy may promote public health behaviors during a pandemic regardless of political orientation. Targeting empathy may be one way to reach individuals with more conservative political beliefs, and it is important to use an evidence-based approach accounting for political party differences in motivated reasoning.

Scientists developing gene drive mosquitoes for vector control must understand how residents of affected areas regard both the problem of mosquito-borne disease and the potential solutions offered by gene drive. This study represents an experiment in public engagement at an early stage of technology development, intended to inform lab scientists about public attitudes toward their research and inspire consideration and conversation about the social ramifications of creating mosquitoes with gene drive. Online focus groups with California residents explored views on mosquito-borne disease risk, current mosquito control methods, and the proposed development and use of different classes of gene drives to control Ae. aegypti. Rather than a dogmatic rejection of genetic engineering or gene drive, many participants expressed pragmatic concerns with cost, control, the ability to narrowly target specific species, and the challenges of mistrust and institutional cooperation. Work like this can inform the alignment of community priorities and the professional priorities of scientists and vector control specialists.

In response to growing concerns regarding mosquito-borne diseases, scientists are developing novel systems of vector control. Early examples include Oxitec's OX513A genetically-engineered mosquito and MosquitoMate's Wolbachia-infected mosquito, and systems using 'gene-drive' are in development. Systems based on genetic engineering are controversial and institutions around the world are grappling with the question of who should have a say in how such technologies are field-tested and used. Based on media coverage and public records, we created comparative timelines of the efforts of Oxitec and MosquitoMate to navigate federal and local governance and bring their products to market in the United States. We analyze these timelines with particular attention to the role of public input in technology governance. These cases illustrate how governance of technology in the US is diverse, complex, and opaque. Further, the public response to proposed field trials of the Oxitec product highlights inconsistencies between public expectations for governance and actual practice. As gene-drive mosquito control products develop, both federal and local agencies will find their legitimacy tested without a better procedure for transparently integrating public input.

Consumer uptake of direct-to-consumer (DTC) DNA ancestry testing is accelerating, yet few empirical studies have examined test impacts on recipients despite the DTC ancestry industry being two decades old. Participants in a longitudinal cohort study of response to health-related DTC genomic testing also received personal DNA ancestry testing at no additional cost. Baseline survey data from the primary study were analyzed together with responses to an additional follow-up survey focused on the response to ancestry results. Ancestry results were generated for 3466 individuals. Of those, 1317 accessed their results, and 322 individuals completed an ancestry response survey, in other words, approximately one in ten who received ancestry testing responded to the survey. Self-reported race/ethnicity was predictive of those most likely to view their results. While 46% of survey responders (N = 147) reported their ancestry results as surprising or unexpected, less than 1% (N = 3) were distressed by them. Importantly, however, 21% (N = 67) reported that their results reshaped their personal identity. Most (81%; N = 260) planned to share results with family, and 12% (N = 39) intended to share results with a healthcare provider. Many (61%; N = 196) reported test benefits (e.g., health insights), while 12% (N = 38) reported negative aspects (e.g., lack of utility). Over half (N = 162) reported being more likely to have other genetic tests in the future. DNA ancestry testing affected individuals with respect to personal identity, intentions to share genetic information with family and healthcare providers, and the likelihood to engage with other genetic tests in the future. These findings have implications for medical care and research, specifically, provider readiness to engage with genetic ancestry information.

BackgroundPrivacy-related concerns can prevent equitable participation in health research by US Indigenous communities. However, studies focused on these communities' views regarding health data privacy, including systematic reviews, are lacking.MethodsWe conducted a systematic literature review analyzing empirical, US-based studies involving American Indian/Alaska Native (AI/AN) and Native Hawaiian or other Pacific Islander (NHPI) perspectives on health data privacy, which we define as the practice of maintaining the security and confidentiality of an individual's personal health records and/or biological samples (including data derived from biological specimens, such as personal genetic information), as well as the secure and approved use of those data.ResultsTwenty-one studies involving 3234 AI/AN and NHPI participants were eligible for review. The results of this review suggest that concerns about the privacy of health data are both prevalent and complex in AI/AN and NHPI communities. Many respondents raised concerns about the potential for misuse of their health data, including discrimination or stigma, confidentiality breaches, and undesirable or unknown uses of biological specimens.ConclusionsParticipants cited a variety of individual and community-level concerns about the privacy of their health data, and indicated that these deter their willingness to participate in health research. Future investigations should explore in more depth which health data privacy concerns are most salient to specific AI/AN and NHPI communities, and identify the practices that will make the collection and use of health data more trustworthy and transparent for participants.

BackgroundWhile there is wide consensus that the public should be consulted about emerging technology early in development, it is difficult to elicit public opinion about innovations unfamiliar to lay audiences. We sought public input on a program of research on genetic engineering to control mosquito vectors of disease that is led by scientists at the University of California and funded by the U.S. Defense Advanced Research Projects Agency (DARPA). In preparation for this effort, we developed a series of narrated slideshows to prompt responses to the development of gene drive mosquito control strategies among lay people. We describe the development and content of these slideshows and evaluate their ability to elicit discussions among focus group participants.MethodsIn developing these materials, we used an iterative process involving input from experts in molecular genetics and vector control. Topics were chosen for their relevance to the goals of the scientists leading the program of research. Significant time was devoted to crafting explanations that would be accessible to uninitiated members of the public but still represent the science accurately. Through qualitative analysis of focus group discussions prompted by the slideshows, we evaluated the success of these slideshows in imparting clear technical information sufficient to inform lay discussion.ResultsThe collaboration resulted in a series of four narrated slideshows that were used to anchor discussions in online focus groups. Many participants described the slideshows as interesting and informative, while also raising concerns and possible risks that were not directly addressed in the material presented. Open-ended comments from participants suggest that the slideshows inspired critical questions, reflection, and conversation about genetically engineered and gene drive mosquitoes. After the final and most technically complex slideshow, however, some respondents made comments suggestive of overwhelm or confusion.ConclusionOur narrated slideshows prompted engaged conversations about genetically engineered mosquitoes among members of the public who were generally naïve to this technology. Narrated slideshows may serve as viable and useful tools for future public engagement on other controversial emerging medical and public health technologies.

We must ensure that trials are scientifically, politically, and socially robust, publicly accountable, and widely transparent

The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of clinician surveys of the clinical utility of rapid genomic sequencing (RGS). The primary end-point-clinician perception that RGS was useful- was met for 154 (77%) of 201 infants. Both positive and negative tests were rated as having clinical utility (42 of 45 [93%] and 112 of 156 [72%], respectively). Physicians reported that RGS changed clinical management in 57 (28%) infants, particularly in those receiving urWGS (p = 0.0001) and positive tests (p < 0.00001). Outcomes of 32 (15%) infants were perceived to be changed by RGS. Positive tests changed outcomes more frequently than negative tests (p < 0.00001). In logistic regression models, the likelihood that RGS was perceived as useful increased 6.7-fold when associated with changes in management (95% CI 1.8-43.3). Changes in management were 10.1-fold more likely when results were positive (95% CI 4.7-22.4) and turnaround time was shorter (odds ratio 0.92, 95% CI 0.85-0.99). RGS seldom led to clinician-perceived confusion or distress among families (6 of 207 [3%]). In summary, clinicians perceived high clinical utility and low likelihood of harm with first-tier RGS of infants in ICUs with diseases of unknown etiology. RGS was perceived as beneficial irrespective of whether results were positive or negative.

Information about genetic engineering (GE) for vector control in the United States is disseminated primarily in English, though non-English speakers are equally, and in some geographic regions even more affected by such technologies. Non-English-speaking publics should have equal access to such information, which is especially critical when the technology in question may impact whole communities. We convened an interdisciplinary workgroup to translate previously developed narrated slideshows on gene drive mosquitoes from English into Spanish, reviewing each iteration for scientific accuracy and accessibility to laypeople. Using the finalised stimuli, we conducted five online, chat-based focus groups with Spanish-speaking adults from California. Overall, participants expressed interest in the topic and were able to summarise the information presented in their own words. Importantly, participants asked for clarification and expressed scepticism about the information presented, indicating critical engagement with the material. Through collaboration with Spanish-speaking scientists engaged in the development of GE methods of vector control, we translated highly technical scientific information into Spanish that successfully engaged Spanish-speaking participants in conversations about this topic. In this manuscript, we document the feasibility of consulting Spanish-speaking publics about a complex emerging technology by drawing on the linguistic diversity of the scientific teams developing the technology.

The pathogenesis of HIV-associated neurocognitive impairment (NCI) may involve iron dysregulation. In 243 HIV-seropositive adults without severe comorbidities, we therefore genotyped 250 variants in 20 iron-related genes and evaluated their associations with magnetic resonance imaging measures of brain structure and metabolites, including measures previously linked to NCI. Multivariable regression analyses examined associations between genetic variants and neuroimaging measures, adjusting for relevant covariates and multiple testing. Exploratory analyses stratified by NCI (Global Deficit Score ≥ 0.5 vs.

BackgroundDespite broad consensus on the importance of community and stakeholder engagement (CSE) for guiding the development, regulation, field testing, and deployment of emerging vector control technologies (such as genetically engineered insects), the types of activities pursued have varied widely, as have the outcomes. We looked to previous CSE efforts for clarity about appropriate methods and goals. Our analysis yielded a typology of CSE, and related vocabulary, that describes distinctions that funders, organizers, and scholars should make when proposing or evaluating CSE.MethodsWe compiled available formal documentation of CSE projects, starting with projects mentioned in interviews with 17 key informants. Major features of these examples, including the initiators, target groups, timing, goals, and methods were identified using qualitative coding. Based on these examples, subcategories were developed for a subset of features and applied to the identified cases of CSE in the documents. Co-occurrence of subcategorized features was examined for patterns.ResultsWe identified 14 documented examples CSE projects, which were comprised of 28 distinct CSE activities. We found no clear patterns with respect to timing. However, we found that grouping examples according to whether initiators or targets could enact the immediate desired outcome could help to clarify relationships between goals, methods, and targets.ConclusionBased on this analysis, we propose a typology that distinguishes three categories of CSE: engagement to inquire -where initiators are empowered to act on information collected through engagement with target groups; engagement to influence -where initiators engage to affect the actions of already-empowered target groups; and engagement to involve -where initiators engage to delegate authority to target groups. The proposed typology can serve as a guide for establishing the goals, identifying appropriate methods, and evaluating and reporting CSE projects by directing attention to important questions to be asked well before determining who to engage and how.

ObjectiveWe sought to present a model of privacy disposition and its development based on qualitative research on privacy considerations in the context of emerging health technologies.Materials and methodsWe spoke to 108 participants across 44 interviews and 9 focus groups to understand the range of ways in which individuals value (or do not value) control over their health information. Transcripts of interviews and focus groups were systematically coded and analyzed in ATLAS.ti for privacy considerations expressed by respondents.ResultsThree key findings from the qualitative data suggest a model of privacy disposition. First, participants described privacy related behavior as both contextual and habitual. Second, there are motivations for and deterrents to sharing personal information that do not fit into the analytical categories of risks and benefits. Third, philosophies of privacy, often described as attitudes toward privacy, should be classified as a subtype of motivation or deterrent.DiscussionThis qualitative analysis suggests a simple but potentially powerful conceptual model of privacy disposition, or what makes a person more or less private. Components of privacy disposition are identifiable and measurable through self-report and therefore amenable to operationalization and further quantitative inquiry.ConclusionsWe propose this model as the basis for a psychometric instrument that can be used to identify types of privacy dispositions, with potential applications in research, clinical practice, system design, and policy.

Background and objectivesThe availability of whole genome sequencing (WGS) is increasing in clinical care, and WGS is a promising tool in diagnostic odyssey cases. Physicians' ability to effectively communicate genomic information with patients, however, is unclear. In this multiperspective study, we assessed physicians' communication of patient genome sequencing information in a diagnostic odyssey case series.MethodsWe evaluated physician communication of genome sequencing results in the context of an ongoing study of the utility of WGS for the diagnosis of rare and idiopathic diseases. A modified version of the Medical Communication Competence Scale was used to compare patients' ratings of their physicians' communication of general medical information to communication of genome sequencing information. Physician self-ratings were also compared with patient ratings.ResultsA total of 47 patients, parents, and physicians across 11 diagnostic odyssey cases participated. In 6 of 11 cases (54%), the patient respondent rated the physician's communication of genome sequencing information as worse than that of general medical information. In 9 of 11 cases (82%), physician self-ratings of communication of genome sequencing information were worse than the patient respondent's rating. Identification of a diagnosis via WGS was positively associated with physician self-ratings (P = .021) but was not associated with patient respondent ratings (P = .959).ConclusionsThese findings reveal that even in diagnostic odyssey cases, in which genome sequencing may be clinically beneficial, physicians may not be well-equipped to communicate genomic information to patients. Future studies may benefit from multiperspective approaches to assessing and understanding physician-patient communication of genome-sequencing information.

In the last decade, genomic medicine education initiatives have surfaced across the spectrum of physician training in order to help address a gap in genomic medicine preparedness among physicians. The approaches are diverse and stem from the belief that 21st century physicians must be proficient in genomic medicine applications as they will be leaders in the precision medicine movement. We conducted a review of literature in genomic medicine education and training for medical students, residents, fellows, and practicing physicians with articles published between June 2015 and January 2018 to gain a picture of the current state of genomic medicine education with a focus on the United States. We found evidence of progress in the development of new and innovative educational programs and other resources aimed at increasing physician knowledge and readiness. Three overarching educational approach themes emerged, including immersive and experiential learning; interdisciplinary and interprofessional education; and electronic- and web-based approaches. This review is not exhaustive, nevertheless, it may inform future directions and improvements for genomic medicine education. Important next-steps include: (i) identifying and studying ways to best implement low-cost dissemination of genomic information; (ii) emphasizing genomic medicine education program evaluation and (iii) incorporating interprofessional and interdisciplinary initiatives. Genomic medicine education and training will become more and more relevant in the years to come as physicians increasingly interact with genomic and other precision medicine technologies.

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS

MotivationWe introduce PRINCESS, a privacy-preserving international collaboration framework for analyzing rare disease genetic data that are distributed across different continents. PRINCESS leverages Software Guard Extensions (SGX) and hardware for trustworthy computation. Unlike a traditional international collaboration model, where individual-level patient DNA are physically centralized at a single site, PRINCESS performs a secure and distributed computation over encrypted data, fulfilling institutional policies and regulations for protected health information.ResultsTo demonstrate PRINCESS' performance and feasibility, we conducted a family-based allelic association study for Kawasaki Disease, with data hosted in three different continents. The experimental results show that PRINCESS provides secure and accurate analyses much faster than alternative solutions, such as homomorphic encryption and garbled circuits (over 40 000× faster).Availability and implementationhttps://github.com/achenfengb/PRINCESS_opensource.Contactshw070@ucsd.edu.Supplementary informationSupplementary data are available at Bioinformatics online.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10 -  9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10 -  9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Anxiety is a risk factor for many adverse neuropsychiatric and socioeconomic outcomes, and has been linked to functional and structural changes in the ventromedial prefrontal cortex (VMPFC). However, the nature of these differences, as well as how they develop in children and adolescents, remains poorly understood. More effective interventions to minimize the negative consequences of anxiety require better understanding of its neurobiology in children. Recent research suggests that structural imaging studies may benefit from clearly delineating between cortical surface area and thickness when examining these associations, as these distinct cortical phenotypes are influenced by different cellular mechanisms and genetic factors. The present study examined relationships between cortical surface area and thickness of the VMPFC and a self-report measure of anxiety (SCARED-R) in 287 youths aged 7-20 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Age and gender interactions were examined for significant associations in order to test for developmental differences. Cortical surface area and thickness were also examined simultaneously to determine whether they contribute independently to the prediction of anxiety. Anxiety was negatively associated with relative cortical surface area of the VMPFC as well as with global cortical thickness, but these associations diminished with age. The two cortical phenotypes contributed additively to the prediction of anxiety. These findings suggest that higher anxiety in children may be characterized by both delayed expansion of the VMPFC and an altered trajectory of global cortical thinning. Further longitudinal studies will be needed to confirm these findings.

Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc. to discuss this question, share viewpoints and propose recommendations. This perspective summarizes that work and identifies some of the obstacles and opportunities that must be considered in translating advances in genomics more widely into the practice of medicine.

Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.

The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal.

IntroductionAdvances in health technology such as genome sequencing and wearable sensors now allow for the collection of highly granular personal health data from individuals. It is unclear how people think about privacy in the context of these emerging health technologies. An open question is whether early adopters of these advances conceptualize privacy in different ways than non-early adopters.PurposeThis study sought to understand privacy attitudes of early adopters of emerging health technologies.MethodsTranscripts from in-depth, semi-structured interviews with early adopters of genome sequencing and health devices and apps were analyzed with a focus on participant attitudes and perceptions of privacy. Themes were extracted using inductive content analysis.ResultsAlthough interviewees were willing to share personal data to support scientific advancements, they still expressed concerns, as well as uncertainty about who has access to their data, and for what purpose. In short, they were not dismissive of privacy risks. Key privacy-related findings are organized into four themes as follows: first, personal data privacy; second, control over personal information; third, concerns about discrimination; and fourth, contributing personal data to science.ConclusionEarly adopters of emerging health technologies appear to have more complex and nuanced conceptions of privacy than might be expected based on their adoption of personal health technologies and participation in open science. Early adopters also voiced uncertainty about the privacy implications of their decisions to use new technologies and share their data for research. Though not representative of the general public, studies of early adopters can provide important insights into evolving attitudes toward privacy in the context of emerging health technologies and personal health data research.

PurposeThe Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene-disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study.MethodsA total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician-scientist review panel, and 17 patients (14.0%) and their family members were enrolled.Results60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene-disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings.ConclusionGenome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking.

Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.

BackgroundMigraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.MethodsWe performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).ResultsWe identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.LimitationsOur study is based on self-reported migraine.ConclusionsNBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

ObjectiveThe NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance.MethodThe NTCB was administered to a sample of 1,020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States.ResultsGeneral additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores.ConclusionsThe results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors.

The field of examining the ethical, legal, and social implications (ELSI) of genetics and genomics in the United States has evolved over the past 30 years. Initially focused on normative and conceptual studies, ELSI research has become more investigational and observational, incorporating social science methods. Engaging the perspectives and voices of those impacted by these technologies, including patients and practitioner communities, is important for enhancing public trust in science and addressing health equity gaps. However, current models for ELSI research and governance are often retrospective and occur too late in the research process to meaningfully inform technology design and implementation. There have been efforts to expand early-stage studies led by technologists and incorporate stakeholder engagement, but more needs to be done to ensure the active involvement of publics in the research process. Initiating empirical ELSI research upstream in the R&D pipeline for emerging technologies could generate significant benefits, including the design of technologies that align with social and ethical considerations and public values. This approach could also enhance the desirability, acceptability, and accessibility of research processes and products within communities. Empirical ELSI should be expanded beyond genomics to other emerging technologies, such as artificial intelligence, and be more formally incorporated into the research innovation ecosystem. This would require cultural shifts in how science is done, increased support for ELSI researchers, and the prioritization of public deliberation and participation. By incorporating upstream empirical ELSI, we can advance responsible innovation and address ethical [Extracted from the article]

Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development.

Structural MRI allows unparalleled in vivo study of the anatomy of the developing human brain. For more than two decades, MRI research has revealed many new aspects of this multifaceted maturation process, significantly augmenting scientific knowledge gathered from postmortem studies. Postnatal brain development is notably protracted and involves considerable changes in cerebral cortical, subcortical, and cerebellar structures, as well as significant architectural changes in white matter fiber tracts (see [12]). Although much work has described isolated features of neuroanatomical development, it remains a critical challenge to characterize the multidimensional nature of brain anatomy, capturing different phases of development among individuals. Capitalizing on key advances in multisite, multimodal MRI, and using cross-validated nonlinear modeling, we demonstrate that developmental brain phase can be assessed with much greater precision than has been possible using other biological measures, accounting for more than 92% of the variance in age. Further, our composite metric of morphology, diffusivity, and signal intensity shows that the average difference in phase among children of the same age is only about 1 year, revealing for the first time a latent phenotype in the human brain for which maturation timing is tightly controlled.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.