Trust in prenatal exome sequencing for expectant families facing unexplained fetal anomalies.

OBJECTIVE: Despite exome sequencing (ES) becoming increasingly incorporated into the prenatal setting, few studies have elucidated motivations for and trust in ES and genomic research among a diverse cohort of patients and their partners. METHODS: This is a qualitative study that involved semi-structured interviews with pregnant or recently pregnant individuals and their partners, interviewed separately, in the setting of ES performed through research for a fetal structural anomaly. All interview transcripts were coded thematically and developed by a multidisciplinary team. RESULTS: Thirty-five individuals participated, the majority of whom (66%) self-identified as a racial or ethnic group underrepresented in genomic research. Many patients and their partners expressed trust in the healthcare system and research process and appreciated the extensive testing for information and closure. There were nonetheless concerns about data privacy and protection for individuals, including those underrepresented, who participated in genomic testing and studies. CONCLUSION: Our findings illustrate important elements of motivation, trust and concern related to prenatal ES performed in the research setting, taking into account the perspectives not only of diverse and underrepresented study participants but also partners of pregnant individuals.

The Next Frontier in Neurology Is In Utero.

This Viewpoint disusses the importance of prioritizing access, safety, and social inclusion for human trials in the paradigm shift toward fetal therapies.

"I Have Fought for so Many Things": Disadvantaged families' Efforts to Obtain Community-Based Services for Their Child after Genomic Sequencing.

BACKGROUND: Families whose child has unexplained intellectual or developmental differences often hope that a genetic diagnosis will lower barriers to community-based therapeutic and support services. However, there is little known about efforts to mobilize genetic information outside the clinic or how socioeconomic disadvantage shapes and constrains outcomes. METHODS: We conducted an ethnographic study with predominantly socioeconomically disadvantaged families enrolled in a multi-year genomics research study, including clinic observations and in-depth interviews in English and Spanish at multiple time points. Coding and thematic development were used to collaboratively interpret fieldnotes and transcripts. RESULTS: Thirty-two families participated. Themes included familial expectations that a genetic diagnosis could be translated into information, understanding, and assistance to improve the quality of a child's day-to-day life. After sequencing, however, genetic information was not readily converted into improved access to services beyond the clinic, with families often struggling to use a genetic diagnosis to advocate for their child. CONCLUSION: Families' ability to use a genetic diagnosis as an effective advocacy tool beyond the clinic was limited by the knowledge and resources available to them, and by the eligibility criteria used by therapeutic service providers' - which focused on clinical diagnosis and functional criteria more than etiologic information. All families undertaking genomic testing, particularly those who are disadvantaged, need additional support to understand the limits and potential benefits of genetic information beyond the clinic.

Privacy, bias and the clinical use of facial recognition technology: A survey of genetics professionals.

Facial recognition technology (FRT) has been adopted as a precision medicine tool. The medical genetics field highlights both the clinical potential and privacy risks of this technology, putting the discipline at the forefront of a new digital privacy debate. Investigating how geneticists perceive the privacy concerns surrounding FRT can help shape the evolution and regulation of the field, and provide lessons for medicine and research more broadly. Five hundred and sixty-two genetics clinicians and researchers were approached to fill out a survey, 105 responded, and 80% of these completed. The survey consisted of 48 questions covering demographics, relationship to new technologies, views on privacy, views on FRT, and views on regulation. Genetics professionals generally placed a high value on privacy, although specific views differed, were context-specific, and covaried with demographic factors. Most respondents (88%) agreed that privacy is a basic human right, but only 37% placed greater weight on it than other values such as freedom of speech. Most respondents (80%) supported FRT use in genetics, but not necessarily for broader clinical use. A sizeable percentage (39%) were unaware of FRT's lower accuracy rates in marginalized communities and of the mental health effects of privacy violations (62%), but most (76% and 75%, respectively) expressed concern when informed. Overall, women and those who self-identified as politically progressive were more concerned about the lower accuracy rates in marginalized groups (88% vs. 64% and 83% vs. 63%, respectively). Younger geneticists were more wary than older geneticists about using FRT in genetics (28% compared to 56% "strongly" supported such use). There was an overall preference for more regulation, but respondents had low confidence in governments' or technology companies' ability to accomplish this. Privacy views are nuanced and context-dependent. Support for privacy was high but not absolute, and clear deficits existed in awareness of crucial FRT-related discrimination potential and mental health impacts. Education and professional guidelines may help to evolve views and practices within the field.

Functional genomics of OCTN2 variants informs protein-specific variant effect predictor for Carnitine Transporter Deficiency.

Genetic variants in SLC22A5, encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of SLC22A5. Interpretation of missense variants of uncertain significance (VUSs) is a major challenge. In this study, we sought to characterize the largest set to date (n = 150) of OCTN2 variants identified in diverse ancestral populations, with the goals of furthering our understanding of the mechanisms leading to OCTN2 loss-of-function (LOF) and creating a protein-specific variant effect prediction model for OCTN2 function. Uptake assays with 14C-carnitine revealed that 105 variants (70%) significantly reduced transport of carnitine compared to wild-type OCTN2, and 37 variants (25%) severely reduced function to less than 20%. All ancestral populations harbored LOF variants; 62% of green fluorescent protein (GFP)-tagged variants impaired OCTN2 localization to the plasma membrane of human embryonic kidney (HEK293T) cells, and subcellular localization significantly associated with function, revealing a major LOF mechanism of interest for CTD. With these data, we trained a model to classify variants as functional (>20% function) or LOF (<20% function). Our model outperformed existing state-of-the-art methods as evaluated by multiple performance metrics, with mean area under the receiver operating characteristic curve (AUROC) of 0.895 ± 0.025. In summary, in this study we generated a rich dataset of OCTN2 variant function and localization, revealed important disease-causing mechanisms, and improved upon machine learning-based prediction of OCTN2 variant function to aid in variant interpretation in the diagnosis and treatment of CTD.

Parental Hopes and Understandings of the Value of Prenatal Diagnostic Genomic Sequencing: A Qualitative Analysis.

Objective: To provide qualitative empirical data on parental expectations of diagnostic prenatal genomic sequencing and the value of the results to families. Methods: We interviewed 15 families-mothers and/or fathers-who had had prenatal genomic sequencing about their expectations and their respective evaluations of the benefits of genomic sequencing. Results: Families' hopes for genetic sequencing clustered around three themes: hoping to identify the cause of the fetal anomaly in a terminated pregnancy; hopes for guidance as to the likely outcome of current pregnancy; and hopes for information to support future family planning. In addition, hopes were discussed in terms of the potential for results to be beneficial in acquiring greater knowledge, while at the same time recognizing that new knowledge may raise more questions. Assessment of the value of sequencing largely mirrored these expectations when positive results seen. Negative results can also be seen as valuable in ruling out a genetic cause and in providing certainty that families had done everything that they could to know about the cause of fetal demise. Conclusion: It would appear that with guidance from genetic counsellors, families were largely able to navigate the many uncertainties of prenatal genomic sequencing and thus see themselves as benefitting from sequencing. However, support structures are essential to guide them through their expectations and interpretations of results to minimize possible harms. Engaging in the process of genomic sequencing was seen as beneficial in of itself to families who would otherwise be left without any options to seek diagnostic answers.

"Let's Just Wait Until She's Born": Temporal Factors That Shape Decision-Making for Prenatal Genomic Sequencing Amongst Families Underrepresented in Genomic Research.

Genomic sequencing has been increasingly utilized for prenatal diagnosis in recent years and this trend is likely to continue. However, decision-making for parents in the prenatal period is particularly fraught, and prenatal sequencing would significantly expand the complexity of managing health risk information, reproductive options, and healthcare access. This qualitative study investigates decision-making processes amongst parents who enrolled or declined to enroll in the prenatal arm of the California-based Program in Prenatal and Pediatric Genome Sequencing (P3EGS), a study in the Clinical Sequencing Evidence-Generating Research (CSER) consortium that offered whole exome sequencing for fetal anomalies with a focus on underrepresented groups in genomic research. Drawing on the views of 18 prenatal families who agreed to be interviewed after enrolling (n = 15) or declining to enroll (n = 3) in P3EGS, we observed that the timing of sequencing, coupled with unique considerations around experiences of time during pregnancy and prenatal testing, intersect with structural supports beyond the clinic to produce preferences for and against prenatal sequencing and to contain the threat of unwelcome, uncertain knowledge. Particularly for those without structural supports, finding out consequential information may be more palatable after the birth, when the first stage of the uncertain future has been revealed. Future research should examine the role of temporality in decision-making around prenatal genomic sequencing across diverse population cohorts, in order to observe more precisely the role that structural barriers play in patient preferences.

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients.

BACKGROUND: Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies. METHODS: A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients' demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression. RESULTS: The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13-9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43-6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18-5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27-6.46, p = 0.011). CONCLUSIONS: Familiarity with postnatal ERT increased respondents' likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT.

The difficulties of broad data sharing in genomic medicine: Empirical evidence from diverse participants in prenatal and pediatric clinical genomics research.

PURPOSE: This study aimed to understand broad data sharing decisions among predominantly underserved families participating in genomic research. METHODS: Drawing on clinic observations, semistructured interviews, and survey data from prenatal and pediatric families enrolled in a genomic medicine study focused on historically underserved and underrepresented populations, this paper expands empirical evidence regarding genomic data sharing communication and decision-making. RESULTS: One-third of parents declined to share family data, and pediatric participants were significantly more likely to decline than prenatal participants. The pediatric population was significantly more socioeconomically disadvantaged and more likely to require interpreters. Opt-in was tied to altruism and participants' perception that data sharing was inherent to research participation. Opt-out was associated with privacy concerns and influenced by clinical staff's presentation of data handling procedures. The ability of participants to make informed choices during enrollment about data sharing was weakened by suboptimal circumstances, which was revealed by poor understanding of data sharing in follow-up interviews as well as discrepancies between expressed participant desires and official recorded choices. CONCLUSION: These empirical data suggest that the context within which informed consent process is conducted in clinical genomics may be inadequate for respecting participants' values and preferences and does not support informed decision-making processes.

Psychiatric genomics, mental health equity, and intersectionality: A framework for research and practice.

The causal mechanisms and manifestations of psychiatric illness cannot be neatly narrowed down or quantified for diagnosis and treatment. Large-scale genome-wide association studies (GWAS) might renew hope for locating genetic predictors and producing precision medicines, however such hopes can also distract from appreciating social factors and structural injustices that demand more socially inclusive and equitable approaches to mental healthcare. A more comprehensive approach begins with recognizing that there is no one type of contributor to mental illness and its duration that should be prioritized over another. We argue that, if the search for biological specificity is to complement the need to alleviate the social distress that produces mental health inequities, psychiatric genomics must incorporate an intersectional dimension to models of mental illness across research priorities, scientific frameworks, and clinical applications. We outline an intersectional framework that will guide all professionals working in the expanding field of psychiatric genomics to better incorporate issues of social context, racial and cultural diversity, and downstream ethical considerations into their work.

Ethical, Legal, and Social Implications of Fetal Gene Therapy.

As fetal gene therapies move from experimental animal models to human in utero phase I clinical trials, there is a need to consider the ethical, legal, and social implications. While fetal gene therapies are attracting more regulatory oversight than previous fetal interventions such as fetal surgery, old sociological questions should be applied to this new context. As health care pathways around fetal therapy are shaped by the ways in which a pregnant person and the fetus are constituted, and as risks and benefits are evaluated, we cannot afford to lose sight of long-term consequences, especially those pertaining to social inclusion.

Opportunities and challenges for the computational interpretation of rare variation in clinically important genes.

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

The impact of public health palliative care interventions on health system outcomes: A systematic review.

BACKGROUND: Public health palliative care interventions are increasingly implemented, with growing recognition of the importance of building evidence to support their utility in end-of-life care. Previous efforts have focused on community outcomes. AIM: To examine the impact of public health palliative care on patterns of health service use at the end of life (primary) and explore which outcomes are being measured within this field of research (secondary). DESIGN: Systematic review of studies reporting qualitative and quantitative data, analysed with a narrative synthesis method. DATA SOURCES: A systematic review conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guideline was undertaken using six electronic databases (MEDLINE, CINAHL, EMBASE, PsycINFO, INFORMIT and COCHRANE) up to February 2020. RESULTS: Searches yielded 2622 unique titles screened for eligibility, resulting in 35 studies measuring outcomes from a public health palliative care approach. Five (14%) studies assessed health system outcomes, and three reported some mixed evidence of impact, including reduced hospital emergency admissions, hospital bed days, hospital costs and increased home deaths. Most studies (86%) instead reported on conceptual (49%), knowledge (40%), programme participation (37%) and/or individual health outcomes (29%). CONCLUSION: The impact of public health palliative care is an evolving area of empirical inquiry with currently only limited evidence that it improves healthcare utilisation outcomes at the end of life, and limited focus on measurement of these outcomes. Further empirical studies are needed to support the reorientation of health services, which remains an important component in realising 'whole of system change' to bring about quality end-of-life care for all.

Relegating Psychosis: Blood Work and "Routine Connection" in the Clozapine Clinic.

This paper attends to the sociality available in the clozapine clinic regimen and suggests that the social dimensions of clozapine treatment may be as important as the biochemical efficacy of clozapine. The clozapine clinic is where people diagnosed with chronic schizophrenia who take the antipsychotic clozapine go for routine monitoring of clozapine side effects, particularly haematological effects. Psychopharmaceutical treatments are often criticized for being reductionistic and dehumanizing, but clozapine clinics offer increased clinical contact in the age of deinstitutionalization. The inadvertent social benefits of biomedically reductive treatments have not previously been ethnographically attended to in the clozapine-only context. Drawing on 18 months of ethnographic fieldwork with 43 clozapine clients and 16 clinical caregivers in two clozapine clinics in the United Kingdom in Australia, I argue that routine clinical attachments in the clozapine clinic can serve a therapeutic role in terms of providing opportunities for clients' health agency, social competence and accountability. This socio-therapeutic quality appeared to be available because the clinical emphasis was not on psychotic illness. It depended, however, on reliable and familiar social exchanges inside the clinic and on the predictability of clinical activity. The importance of unemotional but unfailing relationships and rhythms in the clozapine clinic context echoes cross-cultural findings about how schizophrenia is managed more productively in environments that invite more neutral and equal social exchanges.

Actively Negotiating the Mind-Body Divide: How Clozapine-Treated Schizophrenia Patients Make Health for Themselves.

It is well recognised that antipsychotic treatments impact the whole body, not just the target area of the brain. For people with refractory schizophrenia on clozapine, the gold standard antipsychotic treatment in England and Australia, the separation of mental and physical regimes of health is particularly pronounced, resulting in multiple, compartmentalised treatment registers. Clinicians often focus on the mental health aspects of clozapine use, using physical indicators to determine whether treatment can continue. Our observations of 59 participants in England and Australia over 18 months revealed that patients did not observe this hierarchisation of mental treatments and physical outcomes. Patients often actively engaged in the management of their bodily symptoms, leading us to advance the figure of the active, rather than passive, patient. In our paper, we do not take the position that the facility for active management is a special one utilised only by these patients. We seek instead to draw attention to what is currently overlooked as an ordinary capacity to enact some sort of control over life, even under ostensibly confined and confining circumstances. We argue that clozapine-treated schizophrenia patients utilise the clinical dichotomy between mental and physical domains of health to rework what health means to them. This permits patients to actively manage their own phenomenological 'life projects' (Rapport, I am Dynamite: an Alternative Anthropology of Power, Routledge, London 2003), and forces us to reconsider the notion of clinical giveness of what health means. This making of one's own meanings of health may be critical to the maintenance of a sense of self.

Well-being in clozapine-treated schizophrenia patients: The significance of positive symptoms.

OBJECTIVES: Well-being perception is seldom explored in schizophrenia patients. Recurrent limitations, such as the questionable applicability of gold standard definitions of health and well-being, and fewer tools available to assess well-being, are pronounced in this subpopulation. This cross-sectional study sought to explore potential clinical factors that may predict subjective well-being scores in chronic schizophrenia patients (N=142) receiving clozapine treatment. METHODS: The Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) was used to measure well-being. We correlated SWEMWBS scores and 27 clinically recognized factors, spanning socio-demographics, symptom severity scores, physical health diagnosis, clozapine side effects, habits and prescribed medication. Factors with a p<0.2 correlation were included as a predictors in a linear regression model. RESULTS: Ten factors were included in the linear regression model, however only positive symptom severity was a significant predictor of SWEMWBS score (p<0.0001). CONCLUSIONS: We suggest that greater levels of clinical attention given to positive symptoms compared with other symptoms and aspects of well-being, during biomedical treatment for chronic schizophrenia, may partially explain the finding that only positive symptoms significantly predicted patient perceptions of low well-being.

Genetic diversity of Brazilian Aedes aegypti: patterns following an eradication program.

BACKGROUND: Aedes aegypti is the most important vector of dengue fever in Brazil, where severe epidemics have recently taken place. Ae. aegypti in Brazil was the subject of an intense eradication program in the 1940s and 50s to control yellow fever. Brazil was the largest country declared free of this mosquito by the Pan-American Health Organization in 1958. Soon after relaxation of this program, Ae. aegypti reappeared in this country, and by the early 1980s dengue fever had been reported. The aim of this study is to analyze the present-day genetic patterns of Ae. aegypti populations in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: We studied the genetic variation in samples of 11 widely spread populations of Ae. aegypti in Brazil based on 12 well-established microsatellite loci. Our principal finding is that present-day Brazilian Ae. aegypti populations form two distinct groups, one in the northwest and one in the southeast of the country. These two groups have genetic affinities to northern South American countries and the Caribbean, respectively. This is consistent with what has been reported for other genetic markers such as mitochondrial DNA and allele frequencies at the insecticide resistance gene, kdr. CONCLUSIONS/SIGNIFICANCE: We conclude that the genetic patterns in present day populations of Ae. aegypti in Brazil are more consistent with a complete eradication of the species in the recent past followed by re-colonization, rather than the alternative possibility of expansion from residual pockets of refugia. At least two colonizations are likely to have taken place, one from northern South American countries (e.g., Venezuela) that founded the northwestern group, and one from the Caribbean that founded the southeastern group. The proposed source areas were never declared free of Ae. aegypti.

Origin of the dengue fever mosquito, Aedes aegypti, in California.

Dengue fever is among the most widespread vector-borne infectious diseases. The primary vector of dengue is the Aedes aegypti mosquito. Ae. aegypti is prevalent in the tropics and sub-tropics and is closely associated with human habitats outside its native range of Africa. While long established in the southeastern United States of America where dengue is re-emerging, breeding populations have never been reported from California until the summer of 2013. Using 12 highly variable microsatellite loci and a database of reference populations, we have determined that the likely source of the California introduction is the southeastern United States, ruling out introductions from abroad, from the geographically closer Arizona or northern Mexico populations, or an accidental release from a research laboratory. The power to identify the origin of new introductions of invasive vectors of human disease relies heavily on the availability of a panel of reference populations. Our work demonstrates the importance of generating extensive reference databases of genetically fingerprinted human-disease vector populations to aid public health efforts to prevent the introduction and spread of vector-borne diseases.