Documentation of results and medication prescribing after combinatorial psychiatric pharmacogenetic testing: A case for discrete results.

PURPOSE: Combinatorial pharmacogenetic (PGx) panels intended to aid psychiatric prescribing are available to clinicians. Here, we evaluated the documentation of PGx panel results and subsequent prescribing patterns within a tertiary health care system. METHODS: We performed a query of psychiatry service note text in our electronic health record using 71 predefined PGx terms. Patients who underwent combinatorial PGx testing were identified, and documentation of test results was analyzed. Prescription data following testing were examined for the frequency of prescriptions influenced by genes on the panel along with the medical specialties involved. RESULTS: A total of 341 patients received combinatorial PGx testing, and documentation of results was found to be absent or incomplete for 198 patients (58%). The predominant method of documentation was through portable document formats uploaded to the electronic health record's "Media" section. Among patients with at least 1 year of follow-up, a large majority (194/228, 85%) received orders for medications affected by the tested genes, including 132 of 228 (58%) patients receiving at least 1 non-psychiatric medication influenced by the test results. CONCLUSION: Results from combinatorial PGx testing were poorly documented. Medications affected by these results were often prescribed after testing, highlighting the need for discrete results and clinical decision support.

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. There has been discussion concerning the extent of this obligation in the context of both research and clinical care. Although clinical recommendations have begun to emerge, guidance is lacking on the responsibilities of researchers to inform participants of reinterpreted results. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in November 2018. The workgroup included representatives from the National Society of Genetic Counselors, the Canadian College of Medical Genetics, and the Canadian Association of Genetic Counsellors. The final statement includes twelve position statements that were endorsed or supported by the following organizations: Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Human Genetics Society of Australasia, and National Society of Genetic Counselors.

Sharing in care: engaging care partners in the care and communication of breast cancer patients.

PURPOSE: Family is often overlooked in cancer care. We developed a patient-family agenda setting intervention to engage family in cancer care communication. METHODS: We conducted a pilot randomized controlled trial (NCT03283553) of patients on active treatment for breast cancer and their family "care partner." Intervention dyads (n = 69) completed a self-administered checklist to clarify care partner roles, establish a shared visit agenda, and facilitate MyChart patient portal access. Control dyads (n = 63) received usual care. We assessed intervention acceptability and initial effects from post-visit surveys and MyChart utilization at 6 weeks. RESULTS: At baseline, most patients (89.4%) but few care partners (1.5%) were registered for MyChart. Most patients (79.4%) wanted their care partner to have access to their records and 39.4% of care partners reported accessing MyChart. In completing the checklist, patients and care partners endorsed active communication roles for the care partner and identified a similar visit agenda: most (> 90%) reported the checklist was easy, useful, and recommended it to others. At 6 weeks, intervention (vs control) care partners were more likely to be registered for MyChart (75.4% vs 1.6%; p < 0.001), to have logged in (43.5% vs 0%; p < 0.001) and viewed clinical notes (30.4% vs 0%; p < 0.001), but were no more likely to exchange direct messages with clinicians (1.5% vs 0%; p = 0.175). No differences in patients' MyChart use were observed, but intervention patients more often viewed clinical notes (50.7% vs 9.5%; p < 0.001). CONCLUSIONS: A patient-family agenda setting intervention was acceptable and affected online practices of cancer patients and care partners.

Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background.

PURPOSE: In response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org ) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians. METHODS: We present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics. RESULTS: Formative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a "typical" patient. CONCLUSION: We propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

The Impact of Living with Klinefelter Syndrome: A Qualitative Exploration of Adolescents and Adults.

Klinefelter syndrome (XXY) is a common yet significantly underdiagnosed condition with considerable medical, psychological and social implications. Many health care providers lack familiarity with XXY, resulting in medical management challenges and a limited understanding of the personal impact of the condition. Genetic counselors benefit from understanding the challenges adolescents and men with XXY face to effectively address their medical and psychosocial needs. The purpose of this study was to understand the impact of living with XXY as an adolescent or an adult. Individuals aged 14 to 75 years with self-reported XXY were recruited from online support networks to complete a web-based survey that included open-ended questions. Open-ended responses were coded and analyzed thematically (n = 169 to 210 for each open-ended question). Over half of respondents to the open-ended questions reported challenges in finding health care providers who are knowledgeable about XXY, with many describing an extensive diagnostic odyssey and relief when receiving a diagnosis. Individuals sought support coping with the challenges they face and acknowledgement of the positive aspects of XXY. Recommendations are made for how genetic counseling can enhance quality of life for individuals living with XXY.

Characterizing genetic variants for clinical action.

Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: (1) identify clinically valid genetic variants; (2) decide whether they are actionable and what the action should be; and (3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop.

Technical desiderata for the integration of genomic data into Electronic Health Records.

The era of "Personalized Medicine," guided by individual molecular variation in DNA, RNA, expressed proteins and other forms of high volume molecular data brings new requirements and challenges to the design and implementation of Electronic Health Records (EHRs). In this article we describe the characteristics of biomolecular data that differentiate it from other classes of data commonly found in EHRs, enumerate a set of technical desiderata for its management in healthcare settings, and offer a candidate technical approach to its compact and efficient representation in operational systems.

Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome.

PURPOSE: To determine the prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome. METHODS: Individuals (n = 310) aged 14-75 years with self-reported Klinefelter syndrome were recruited from regional and national support networks to complete a web-based survey. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Perceived consequences (Illness Perceptions Questionnaire), perceived stigma (Perceived Social Stigmatization Scale), and coping (Ways of Coping Checklist-Revised) were also measured and evaluated as correlates of depressive symptoms. RESULTS: Overall, 68.8% of the study participants reported clinically significant levels of depressive symptoms as indicated by a Center for Epidemiologic Studies Depression Scale score ≥16. The use of emotion-focused coping strategies (P < 0.01), perceptions of stigmatization (P < 0.01), perceived negative consequences of Klinefelter syndrome (P < 0.01), and the importance of having children in the future (P < 0.05) were all significantly associated with depressive symptoms. CONCLUSIONS: Individuals with Klinefelter syndrome may be at increased risk for depression. Routine screening for depressive symptoms and appropriate referral and evaluation may be warranted.

Patient reactions to personalized medicine vignettes: an experimental design.

PURPOSE: Translational investigation on personalized medicine is in its infancy. Exploratory studies reveal attitudinal barriers to "race-based medicine" and cautious optimism regarding genetically personalized medicine. This study describes patient responses to hypothetical conventional, race-based, or genetically personalized medicine prescriptions. METHODS: Three hundred eighty-seven participants (mean age = 47 years; 46% white) recruited from a Baltimore outpatient center were randomized to this vignette-based experimental study. They were asked to imagine a doctor diagnosing a condition and prescribing them one of three medications. The outcomes are emotional response to vignette, belief in vignette medication efficacy, experience of respect, trust in the vignette physician, and adherence intention. RESULTS: Race-based medicine vignettes were appraised more negatively than conventional vignettes across the board (Cohen's d = -0.51-0.57-0.64, P < 0.001). Participants rated genetically personalized comparably with conventional medicine (-0.14-0.15-0.17, P = 0.47), with the exception of reduced adherence intention to genetically personalized medicine (Cohen's d = -0.38-0.41-0.44, P = 0.009). This relative reluctance to take genetically personalized medicine was pronounced for racial minorities (Cohen's d = -0.38-0.31-0.25, P = 0.02) and was related to trust in the vignette physician (change in R = 0.23, P < 0.001). CONCLUSIONS: This study demonstrates a relative reluctance to embrace personalized medicine technology, especially among racial minorities, and highlights enhancement of adherence through improved doctor- patient relationships.

Physician practices in evaluation and treatment of patients with generalized joint hypermobility and bleeding.

The association between bleeding and joint hypermobility may not be as diagnostically obvious in patients with milder connective tissue disorders. We surveyed members of the Hemostasis and Thrombosis Research Society regarding their knowledge, evaluation, and management practices in patients with generalized hypermobility spectrum disorder/hypermobile Ehlers-Danlos syndrome (hEDS) and bleeding symptoms. The objectives of this study were to (1) evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS and (2) determine future education and research priorities regarding bleeding symptoms within this population. Evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS. Determine future education and research priorities regarding bleeding symptoms within this population. A web-based survey was sent to Hemostasis and Thrombosis Research Society physician members. Physician demographics, preferred evaluation for hEDS, management of bleeding episodes, and referral patterns were collected and descriptive statistics were performed. Only two-thirds of respondents reported evaluating for hypermobility, despite all respondents being aware of the association with bleeding. There were significant variations in referral patterns for genetic counseling, diagnostic evaluation, and management of nonhematologic symptoms. There were also significant variations in reported medical homes for this patient population. Research prioritization included understanding the evolution of bleeding symptoms with age in this population as well as the development of functional tests to identify the molecular mechanism of bleeding and the development of novel hemostatic agents for this population. Results from 33 respondents show differing physician practices regarding the evaluation and management of bleeding in hypermobile patients. Many physicians suggested further research priorities to include studying the natural history of the disease and development of functional diagnostic testing as well as targeted therapeutic options in this patient population.

A randomized intervention involving family to improve communication in breast cancer care.

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

Application of a framework to guide genetic testing communication across clinical indications.

BACKGROUND: Genetic information is increasingly relevant across healthcare. Traditional genetic counseling (GC) may limit access to genetic information and may be more information and support than some individuals need. We report on the application and clinical implications of a framework to consistently integrate genetics expertise where it is most useful to patients. METHODS: The Clinical Genome Resource's (ClinGen) Consent and Disclosure Recommendations (CADRe) workgroup designed rubrics to guide pre- and post-genetic test communication. Using a standard set of testing indications, pre- and post-test rubrics were applied to 40 genetic conditions or testing modalities with diverse features, including variability in levels of penetrance, clinical actionability, and evidence supporting a gene-disease relationship. Final communication recommendations were reached by group consensus. RESULTS: Communication recommendations were determined for 478 unique condition-indication or testing-indication pairs. For half of the conditions and indications (238/478), targeted discussions (moderate communication depth) were the recommended starting communication level for pre- and post-test conversations. Traditional GC was recommended pre-test for adult-onset neurodegenerative conditions for individuals with no personal history and post-test for most conditions when genetic testing revealed a molecular diagnosis as these situations are likely higher in complexity and uncertainty. A brief communication approach was recommended for more straightforward conditions and indications (e.g., familial hypercholesterolemia; familial variant testing). CONCLUSIONS: The CADRe recommendations provide guidance for clinicians in determining the depth of pre- and post-test communication, strategically aligning the anticipated needs of patients with the starting communication approach. Shorter targeted discussions or brief communications are suggested for many tests and indications. Longer traditional GC consultations would be reserved for patients with more complex and uncertain situations where detailed information, education, and psychological support can be most beneficial. Future studies of the CADRe communication framework will be essential for determining if CADRe-informed care supports quality patient experience while improving access to genetic information across healthcare.

Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome.

Despite well-established clinical associations between Hypermobile Ehlers-Danlos syndrome (hEDS) and postural orthostatic tachycardia syndrome (POTS), the precise prevalence is unknown. We therefore evaluated for hEDS in 91 POTS participants using the 2017 hEDS diagnostic checklist, which has three major criteria: 1) generalized joint hypermobility (Beighton score), 2) systemic features, family history, and 3) absence of exclusion criteria. Overall, 28 out of 91 POTS participants (31%) met clinical criteria for hEDS. An additional 24% of participants had generalized joint hypermobility without meeting hEDS criteria. Identifying the prevalence of hEDS in POTS is important for understanding possible mechanisms connecting these two syndromes.

Symptomatic Joint Hypermobility: The Hypermobile Type of Ehlers-Danlos Syndrome and the Hypermobility Spectrum Disorders.

Joint hypermobility may be syndromic or nonsyndromic, asymptomatic or symptomatic. However, asymptomatic joint hypermobility can cause repetitive use injury, alter biomechanics, or become symptomatic later in life. Symptomatic joint hypermobility can result from soft tissue injury or muscular strain caused by muscular imbalance. Treatment is straightforward once joint hypermobility is recognized. Generalized joint hypermobility can be assessed using a standardized in-office examination. Generalized joint hypermobility may also be a feature of a heritable connective tissue disorder with other systemic findings. Therefore, assessing joint hypermobility in the context of musculoskeletal complaints may lead to recognizing systemic manifestations and allow treatment accordingly.

Twenty questions in genetic medicine--an assessment of World Wide Web databases for genetics information at the point of care.

PURPOSE: The aim of this article was to determine the accuracy and efficiency of World Wide Web ("Web") resources to help nongeneticists answer four clinical questions about each of five common genetic conditions. METHODS: Correct answers were established by literature review. Two open-access genetics resources and seven general subscription resources were reviewed. Scoring criteria were established to define complete, partial, vague, inconsistent, not found, and wrong answers. The main outcome measures were number of answers found, accuracy, and completeness of answers. Efficiency (time per answer found) was a secondary measure. RESULTS: Overall, the databases contained complete answers 33.3% of the time but contained no information as frequently (33.9%). The best database had complete answers 70% of the time, whereas the worst contained no complete answers. Five of the seven subscription databases had a total of eight wrong answers. The other two subscription databases and the two open-access genetics databases had no wrong answers. Search time ranged from 3.2 to 18.3 minutes per complete answer. CONCLUSIONS: Nongeneticist providers do not have a Web resource that is accessible, accurate, and efficient to answer genetic questions that might arise in practice.

Factors associated with adaptation to Klinefelter syndrome: the experience of adolescents and adults.

OBJECTIVE: The purpose of this study was to understand the impact of living with Klinefelter syndrome (XXY) as an adolescent or an adult and to examine the factors that contribute to adaptation. METHODS: Individuals (n = 310) aged 14-75 years with self-reported XXY were recruited from online support networks to complete a self-administered survey. Perceived consequences, perceived severity, perceived stigma, and coping were measured and evaluated as correlates of adaptation. RESULTS: The use of problem-focused coping strategies was positively correlated with adaptation (p < 0.01) and age was negatively correlated with adaptation (p < 0.05). CONCLUSION: The majority of participants reported significant negative consequences of XXY, including infertility, psychological co-morbidities and differences in appearance. How participants coped with their negative appraisals was the greatest predictor of adaptation. PRACTICE IMPLICATIONS: Interventions designed to help individuals reframe negative appraisals, to increase perceived manageability of the challenges of living with XXY, and to facilitate effective coping may improve adaptation among individuals with XXY.

Insomnia in Cornelia de Lange syndrome.

OBJECTIVE: Up to 55% of patients with Cornelia de Lange Syndrome (CdLS) experience sleep disturbance. Prior evaluation of children without CdLS with similar intellectual disability and self-injurious behavior suggests that sleep disturbances may be related to insomnia or circadian issues. METHODS: Caregivers of 31 patients (19 children) with CdLS completed a sleep history questionnaire focused on sleep patterns and evening sleep behavior to screen for signs and symptoms of insomnia and circadian rhythm disorders. RESULTS: The mean age of participants was 14.5 years (range 0.6-37). Major difficulty in falling asleep (75% pediatric, 33% adult) and staying asleep (52% pediatric, 33% adult) was noted. Overall, time to sleep onset was 27.0 ± 17.6 min, however in those with stated sleep onset difficulty, average time to sleep was 37.8 ± 16.4 min (p=0.002). The mean number of pediatric nighttime awakenings was 1.5 overall and 2.1 in those with stated sleep maintenance difficulties versus 0.7 and 1.5 respectively in adults. Children with CdLS tended to fall back asleep slower (61.8 min) than adults (14.9 min), but none of the comparisons between adult and pediatric sleep measures were significant. Greater than half of participants reported a family member with a possible circadian rhythm disorder. CONCLUSIONS: Symptoms suggestive of insomnia or circadian rhythm disorder are prevalent in this cohort of children and adults with CdLS. Adults may have less severe symptoms than children, suggesting some improvement over time although this study is underpowered for this analysis. Further studies are necessary to better characterize sleep disturbance in the CdLS population.