Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today.

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.

Health care utilization and behavior changes after workplace genetic testing at a large US health care system.

PURPOSE: This study explored employee health behavior changes and health care utilization after workplace genetic testing (wGT). Wellness-program-associated wGT seeks to improve employee health, but the related health implications are unknown. METHODS: Employees of a large US health care system offering wGT (cancer, heart disease, and pharmacogenomics [PGx]) were sent electronic surveys. Self-reported data from those who received test results were analyzed. Descriptive statistics characterized responses, whereas logistic regression analyses explored correlates of responses to wGT. RESULTS: 53.9% (n = 418/776) of respondents (88.3% female, mean age = 44 years) reported receiving wGT results. 12.0% (n = 48/399) received results indicating increased risk (IR) of cancer, 9.5% (n = 38/398) had IR of heart disease, and 31.4% (n = 125/398) received informative PGx results. IR results for cancer and/or heart disease (n = 67) were associated with health behavior changes (adjusted odds ratio: 3.23; 95% CI 1.75, 6.13; P < .001) and health care utilization (adjusted odds ratio: 8.60; 95% CI 4.43, 17.5; P < .001). Informative PGx results (n = 125) were associated with medication changes (PGx-informative: 15.2%; PGx-uninformative: 4.8%; P = .002). CONCLUSION: This study explored employee responses to wGT, contributing to the understanding of the ethical and social implications of wGT. Receiving IR results from wGT may promote health behavior changes and health care utilization in employees.

The goldilocks conundrum: Disclosing discrimination risks in informed consent.

Informed consent is a foundational ethical and legal principle in human subjects research and clinical care. Yet, there is extensive debate over how much information must be disclosed to meet ethical goals and legal requirements, especially about non-medical risks. In this online, survey-based experiment of a diverse sample of the US general population, we explored one aspect of this debate by testing whether the level of detail included in informed consent regarding genetic anti-discrimination protections alters individuals' willingness to participate in a hypothetical research study and their concerns regarding genetic discrimination. Participants were randomized to receive sample informed consent language with one of three levels of disclosure regarding the protections and limitations of the Genetic Information Nondiscrimination Act (GINA). Our sample (n = 1,195) had a mean age of 45.9 (SD = 17.9) years and 40% with ≤high school education. Participants were 51.3% female and 36.7% non-Hispanic White. On average, those who received consent language with none of GINA's limitations highlighted were more willing to participate than those who were warned about various gaps in GINA. They also had significantly lower perceived risk of discrimination than those presented with the most information about limitations. Our study found that providing more comprehensive information about GINA notably lessened willingness to participate in the hypothetical studies, highlighting the need for clinicians and researchers to thoughtfully consider how to disclose anti-discrimination risks in informed consent.

The persistent lack of knowledge and misunderstanding of the Genetic Information Nondiscrimination Act (GINA) more than a decade after passage.

PURPOSE: More than a decade after the Genetic Information Nondiscrimination Act (GINA) was passed, there is a paucity of research on the general public's awareness of GINA. This study's objective was to assess knowledge of GINA and concerns of genetic discrimination. METHODS: A quota-based sample of US adults (N = 421) was recruited via Qualtrics Research Services to complete an online survey. RESULTS: Overall, participants had a mean age of 43.1 (SD = 13.9), 51.8% identified as female, 63.1% identified as non-Hispanic White, and 38.4% had ≥4-year college degree. Respondents reported relatively low subjective knowledge of GINA (M = 3.10, SD = 1.98; 7-point Likert scale). Among respondents reporting high subjective knowledge of GINA (16.2%), 92.6% incorrectly reported or did not know that GINA does not covers life, long-term care, and disability insurance, and this number was 82.4% for auto or property insurance. Respondents were relatively likely to decline genetic testing due to concerns about results being used to determine eligibility for employment (M = 4.68, SD = 1.89) or health insurance (M = 4.94, SD = 1.73). There were few consistent demographic associations with either subjective or objective knowledge of GINA. CONCLUSION: This study highlights continued public concern about genetic discrimination and a lack of awareness and understanding of GINA and its scope of protections.

Genetic counseling, virtual visits, and equity in the era of COVID-19 and beyond.

Overnight, as a result of the COVID-19 pandemic, telehealth rapidly transitioned from limited application to widespread implementation. The field of genetic counseling was well positioned to make this transition to virtual care since there is generally less of a need for patients to be seen in-person for physical exams or urgent care. Going forward, virtual visits will presumably become a mainstay in the provision of genetic services and it is anticipated that clinics will adopt "hybrid" models with both in-person and virtual visit options. This commentary highlights the successes and challenges in the rapid implementation of virtual visits, focusing on who has benefited versus who has been challenged or left behind. We also discuss genetic testing considerations, including the additional steps required for patients and clinicians when testing is ordered outside of the clinical setting, which can result in delays or a lack of testing altogether. Future research considerations are presented to address the needs among the most vulnerable and help ensure equitable access and benefit.

A survey of aortic disease biorepository participants' preferences for return of research genetic results.

There is ongoing debate on whether and what research genetic results to return to study participants. To date, no study in this area has focused on aortopathy populations despite known genes that are clinically actionable. Participants (n = 225, 79% male, mean age = 61 years) with an aortopathy were surveyed to assess preferences for receiving research genetic results. Participants were 'very' or 'extremely likely' to want results for pathogenic variants in aortopathy genes with implications for family members (81%) or that would change medical management (76%). Similarly, participants were 'very' or 'extremely likely' to want actionable secondary findings related to cancer (75%) or other cardiac diseases (70%). Significantly lower interest was observed for non-actionable findings-pathogenic variants in aortopathy genes that would not change medical management (51%) and variants of uncertain significance (38%) (p < .0001). Higher health and genomic literacy were positively associated with interest in actionable findings. Most participants (>63%) were accepting of any means of return; however, a substantial minority (18%-38%) deemed certain technological means unacceptable (e.g., patient portal). Over 90% of participants reported that a range of health professionals, including cardiovascular specialists, genetics specialists, and primary care providers, were acceptable to return results. Participants with aortopathies are highly interested in research genetic results perceived to be medically actionable for themselves or family members. Participants are accepting of a variety of means for returning results. Findings suggest that research participants should be asked what results are preferred at time of informed consent and that genetic counseling may clarify implications of results that are not personally medically actionable.

Genetic counseling following direct-to consumer genetic testing: Consumer perspectives.

As the use and scope of direct-to-consumer genetic testing (DTC GT), also becoming known as consumer-driven genetic testing, increases, consumers may seek genetic counseling to understand their results and determine healthcare implications. In this study, we interviewed individuals who sought genetic counseling after receiving DTC GT results to explore their motivations, expectations, and experiences. Participants were recruited from the Impact of Personal Genomics (PGen) Study, a longitudinal cohort study of DTC GT customers. We interviewed 15 participants (9 females, mean age = 38 years) by telephone and analyzed the double-coded transcripts using qualitative methods. Motivations for genetic counseling included family and personal health histories, concern and confusion about results, and information-seeking; of note, one-third of our interview participants had Ehlers-Danlos syndrome Type III (hypermobility type). Expectations of genetic counseling sessions were high. Participants generally saw DTC GT results as valid and potentially impactful for their healthcare, wanted more thorough explanations in "layman's terms," a pooling of their results with their family and personal health history and a "game plan." Several participants had already accessed online resources, including resources typically used by genetics clinicians. Our results point to several elements of a successful DTC GT genetic counseling session: 1) effective contracting when starting the clinic visit, especially determining motivations for genetic counseling, results that are concerning/confusing and resources already accessed; 2) ascertainment and management of expectations and clearly communicating if and why all results may not be reviewed; 3) explaining how DTC GT differs from clinical genetic testing and why additional testing may not be indicated and 4) listening to (not dismissing) patient concerns about their results. For those patients who seek genetic counseling about DTC GT results, the findings from our study can help inform case preparation and provision of genetic counseling.

Genetic testing for neurodegenerative diseases: Ethical and health communication challenges.

Advances in genomic science are informing an expansion of genetic testing for neurodegenerative diseases, which can be used for diagnostic and predictive purposes and performed in both medical and consumer genomics settings. Such testing-which is often for severe and incurable conditions like Huntington's, Alzheimer's, and Parkinson's diseases-raises important ethical and health communication challenges. This review addresses such challenges in the contexts of clinical, research, and direct-to-consumer genetic testing; these include informed consent, risk estimation and communication, potential benefits and psychosocial harms of genetic information (e.g., genetic discrimination), access to services, education and workforce needs, and health policies. The review also highlights future areas of likely growth in the field, including polygenic risk scores, use of genetic testing in clinical trials, and return of individual research results.

40 years and beyond for the National Society of Genetic Counselors: Reflections on genetic counseling practice.

The National Society of Genetic Counselors (NSGC) was established in 1979 and has grown from a small dedicated group of genetic counselors to over 5,000 certified genetic counselors in 2019. During this time period, there have been tremendous advances in the practice of genetic counseling, the availability of genetic testing, and the use of technology. These advances have significantly changed our roles and responsibilities and have contributed to the expansion and diversification of our field in clinical and non-clinical work settings. The launch of genetic counseling services in prenatal, pediatric, and adult genetics clinics has expanded to many medical specialties. Genetic counselors are also working in industry, public health, policy, education, research, and other work settings. With growth into new areas and the significant increase in the number of practitioners, genetic counselors have established themselves professionally and created opportunities where they can not only contribute to the delivery of quality genetic services, but lead the way. The counseling skills that are a core part of training as genetic counselors will continue to have broad application in diverse work settings and roles. Looking to the future, genetic counselors need to proactively consider tasks that artificial intelligence and other technologies can accomplish so that genetic counselors have the bandwidth to use their expertise to successfully and efficiently meet the growing demands for genetic counseling services. During the 40th anniversary celebration at the 2019 NSGC Annual Conference, three of NSGC's past presidents reflected on the early years of NSGC and clinical practice, recognized key accomplishments and where the profession stands today, and shared thoughts about the future of genetic counseling. Videos of the actual talks can be accessed by internet search 'NSGC Celebrates 40 Years' (https://www.nsgc.org/p/bl/et/blogid=53&blogaid=1162). A timeline of the genetic counseling profession is available at https://www.nsgc.org/page/nsgc-timeline.

Interpretations of the Term "Actionable" when Discussing Genetic Test Results: What you Mean Is Not What I Heard.

In genomic medicine, the familiarity and inexactness of the term "actionable" can lead to multiple interpretations and mistaken beliefs about realistic treatment options. As part of a larger study focusing on public attitudes toward policies for the return of secondary genomic results, we looked at how members of the lay public interpret the term "medically actionable" in the context of genetic testing. We also surveyed a convenience sample of oncologists as part of a separate study and asked them to define the term "medically actionable." After being provided with a definition of the term, 21 out of 60 (35%) layperson respondents wrote an additional action not specified in the provided definition (12 mentioned "cure" and 9 mentioned environment or behavioral change) and 17 (28%) indicated "something can be done" with no action specified. In contrast, 52 surveyed oncologists did not mention environment, behavioral change, or cure. Based on our findings, we propose that rather than using the term "actionable" alone, providers should also say "what they mean" to reduce miscommunication and confusion that could negatively impact medical decision-making. Lastly, to guide clinicians during patient- provider discussion about genetic test results, we provide examples of phrasing to facilitate clearer communication and understanding of the term "actionable."

A randomized controlled trial of disclosing genetic risk information for Alzheimer disease via telephone.

PurposeTelephone disclosure of genetic test results can improve access to services. To date, studies of its impact have focused on return of Mendelian risk information, principally hereditary cancer syndromes.MethodsIn a multisite trial of Alzheimer disease genetic risk disclosure, asymptomatic adults were randomized to receive test results in person or via telephone. Primary analyses examined patient outcomes 12 months after disclosure.ResultsData from 257 participants showed that telephone disclosure occurred 7.4 days sooner and was 30% shorter, on average, than in-person disclosure (both P < 0.001). Anxiety and depression scores were well below cutoffs for clinical concern across protocols. Comparing telephone and in-person disclosure protocols, 99% confidence intervals of mean differences were within noninferiority margins on scales assessing anxiety, depression, and test-related distress, but inconclusive about positive impact. No differences were observed on measures of recall and subjective impact. Subanalyses supported noninferiority on all outcomes among apolipoprotein E (APOE) ɛ4-negative participants. Subanalyses were inconclusive for APOE ɛ4-positive participants, although mean anxiety and depression scores were still well below cutoffs for clinical concern.ConclusionTelephone disclosure of APOE results and risk for Alzheimer disease is generally safe and helps providers meet demands for services, even when results identify an increased risk for disease.

A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc.

Development of a Streamlined Work Flow for Handling Patients' Genetic Testing Insurance Authorizations.

Obtaining genetic testing insurance authorizations for patients is a complex, time-involved process often requiring genetic counselor (GC) and physician involvement. In an effort to mitigate this complexity and meet the increasing number of genetic testing insurance authorization requests, GCs formed a novel partnership with an industrial engineer (IE) and a patient services associate (PSA) to develop a streamlined work flow. Eight genetics clinics and five specialty clinics at the University of Michigan were surveyed to obtain benchmarking data. Tasks needed for genetic testing insurance authorization were outlined and time-saving work flow changes were introduced including 1) creation of an Excel password-protected shared database between GCs and PSAs, used for initiating insurance authorization requests, tracking and follow-up 2) instituting the PSAs sending GCs a pre-clinic email noting each patients' genetic testing insurance coverage 3) inclusion of test medical necessity documentation in the clinic visit summary note instead of writing a separate insurance letter and 4) PSAs development of a manual with insurance providers and genetic testing laboratories information. These work flow changes made it more efficient to request and track genetic testing insurance authorizations for patients, enhanced GCs and PSAs communication, and reduced tasks done by clinicians.

The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re-evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family's clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that "the patient" can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient's daughter's pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient's husband's internet search of his wife's clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re-evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.

Utilization of Genetic Counseling after Direct-to-Consumer Genetic Testing: Findings from the Impact of Personal Genomics (PGen) Study.

Direct-to-consumer personal genomic testing (DTC-PGT) results lead some individuals to seek genetic counseling (GC), but little is known about these consumers and why they seek GC services. We analyzed survey data pre- and post-PGT from 1026 23andMe and Pathway Genomics customers. Participants were mostly white (91%), female (60%), and of high socioeconomic status (80% college educated, 43% household income of ≥$100,000). After receiving PGT results, 43 participants (4%) made or planned to schedule an appointment with a genetic counselor; 390 (38%) would have used in-person GC had it been available. Compared to non-seekers, GC seekers were younger (mean age of 38 vs 46 years), more frequently had children <18 (26% vs 16%), and were more likely to report previous GC (37% vs 7%) and genetic testing (30% vs 15%). In logistic regression analysis, seeking GC was associated with previous GC use (OR = 6.5, CI = 3.1-13.8), feeling motivated to pursue DTC-PGT for health reasons (OR = 4.3, CI = 1.8-10.1), fair or poor self-reported health (OR = 3.1, CI = 1.1-8.3), and self-reported uncertainty about the results (OR = 1.8, CI = 1.1-2.7). These findings can help GC providers anticipate who might seek GC services and plan for clinical discussions of DTC-PGT results.

Public's Views toward Return of Secondary Results in Genomic Sequencing: It's (Almost) All about the Choice.

The therapeutic use of genomic sequencing creates novel and unresolved questions about cost, clinical efficacy, access, and the disclosure of sequencing results. The disclosure of the secondary results of sequencing poses a particularly challenging ethical problem. Experts disagree about which results should be shared and public input - especially important for the creation of disclosure policies - is complicated by the complex nature of genetics. Recognizing the value of deliberative democratic methods for soliciting informed public opinion on matters like these, we recruited participants from a clinical research site for an all-day deliberative democracy (DD) session. Participants were introduced to the clinical and ethical issues associated with genomic sequencing, after which they discussed the tradeoffs and offered their opinions about policies for the return of secondary results. Participants (n = 66; mean age = 57 (SD = 15); 70% female; 76% white) were divided into 10 small groups (5 to 8 participants each) allowing interactive deliberation on policy options for the return of three categories of secondary results: 1) medically actionable results; 2) risks for adult-onset disorders identified in children; and 3) carrier status for autosomal recessive disorders. In our qualitative analysis of the session transcripts, we found that while participants favored choice and had a preference for making information available, they also acknowledged the risks (and benefits) of learning such information. Our research reveals the nuanced reasoning used by members of the public when weighing the pros and cons of receiving genomic information, enriching our understanding of the findings of surveys of attitudes regarding access to secondary results.

Effect of Public Deliberation on Attitudes toward Return of Secondary Results in Genomic Sequencing.

The increased use of genomic sequencing in clinical diagnostics and therapeutics makes imperative the development of guidelines and policies about how to handle secondary findings. For reasons both practical and ethical, the creation of these guidelines must take into consideration the informed opinions of the lay public. As part of a larger Clinical Sequencing Exploratory Research (CSER) consortium project, we organized a deliberative democracy (DD) session that engaged 66 participants in dialogue about the benefits and risks associated with the return of secondary findings from clinical genomic sequencing. Participants were educated about the scientific and ethical aspects of the disclosure of secondary findings by experts in medical genetics and bioethics, and then engaged in facilitated discussion of policy options for the disclosure of three types of secondary findings: 1) medically actionable results; 2) adult onset disorders found in children; and 3) carrier status. Participants' opinions were collected via surveys administered one month before, immediately following, and one month after the DD session. Post DD session, participants were significantly more willing to support policies that do not allow access to secondary findings related to adult onset conditions in children (Χ 2 (2, N = 62) = 13.300, p = 0.001) or carrier status (Χ 2 (2, N = 60) = 11.375, p = 0.003). After one month, the level of support for the policy denying access to secondary findings regarding adult-onset conditions remained significantly higher than the pre-DD level, although less than immediately post-DD (Χ 2 (1, N = 60) = 2.465, p = 0.041). Our findings suggest that education and deliberation enhance public appreciation of the scientific and ethical complexities of genome sequencing.

Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized Trial.

BACKGROUND: Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information. OBJECTIVE: To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD). DESIGN: Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917). SETTING: 4 teaching hospitals. PARTICIPANTS: 257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative. INTERVENTION: Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only). MEASUREMENTS: Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months. RESULTS: At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, -1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, -1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ±5 points. Among carriers of the APOE ε4 allele, distress was lower in the AD+CAD groups (difference, -4.8 [CI, -8.6 to -1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype. LIMITATIONS: Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants. CONCLUSION: Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk. PRIMARY FUNDING SOURCE: National Human Genome Research Institute.