Errors in genome sequencing result disclosures: A randomized controlled trial comparing neonatology non-genetics healthcare professionals and genetic counselors.

PURPOSE: We compared the rate of errors in genome sequencing (GS) result disclosures by genetic counselors (GC) and trained non-genetics healthcare professionals (NGHPs) in SouthSeq, a randomized trial utilizing GS in critically ill infants. METHODS: Over 400 recorded GS result disclosures were analyzed for major and minor errors. We used Fisher's exact test to compare error rates between GCs and NGHPs and performed a qualitative content analysis to characterize error themes. RESULTS: Major errors were identified in 7.5% of disclosures by NGHPs and in no disclosures by GCs. Minor errors were identified in 32.1% of disclosures by NGHPs and in 11.4% of disclosures by GCs. Although most disclosures lacked errors, NGHPs were significantly more likely to make any error than GCs for all result types (positive, negative, or uncertain). Common major error themes include omission of critical information, overstating a negative result, and overinterpreting an uncertain result. The most common minor error was failing to disclose negative secondary findings. CONCLUSION: Trained NGHPs made clinically significant errors in GS result disclosures. Characterizing common errors in result disclosure can illuminate gaps in education to inform the development of future genomics training and alternative service delivery models.

Parents' Perspectives on the Utility of Genomic Sequencing in the Neonatal Intensive Care Unit.

BACKGROUND: It is critical to understand the wide-ranging clinical and non-clinical effects of genome sequencing (GS) for parents in the NICU context. We assessed parents' experiences with GS as a first-line diagnostic tool for infants with suspected genetic conditions in the NICU. METHODS: Parents of newborns (N = 62) suspected of having a genetic condition were recruited across five hospitals in the southeast United States as part of the SouthSeq study. Semi-structured interviews (N = 78) were conducted after parents received their child's sequencing result (positive, negative, or variants of unknown significance). Thematic analysis was performed on all interviews. RESULTS: Key themes included that (1) GS in infancy is important for reproductive decision making, preparing for the child's future care, ending the diagnostic odyssey, and sharing results with care providers; (2) the timing of disclosure was acceptable for most parents, although many reported the NICU environment was overwhelming; and (3) parents deny that receiving GS results during infancy exacerbated parent-infant bonding, and reported variable impact on their feelings of guilt. CONCLUSION: Parents reported that GS during the neonatal period was useful because it provided a "backbone" for their child's care. Parents did not consistently endorse negative impacts like interference with parent-infant bonding.

Education and Training of Non-Genetics Providers on the Return of Genome Sequencing Results in a NICU Setting.

To meet current and expected future demand for genome sequencing in the neonatal intensive care unit (NICU), adjustments to traditional service delivery models are necessary. Effective programs for the training of non-genetics providers (NGPs) may address the known barriers to providing genetic services including limited genetics knowledge and lack of confidence. The SouthSeq project aims to use genome sequencing to make genomic diagnoses in the neonatal period and evaluate a scalable approach to delivering genome sequencing results to populations with limited access to genetics professionals. Thirty-three SouthSeq NGPs participated in a live, interactive training intervention and completed surveys before and after participation. Here, we describe the protocol for the provider training intervention utilized in the SouthSeq study and the associated impact on NGP knowledge and confidence in reviewing, interpreting, and using genome sequencing results. Participation in the live training intervention led to an increased level of confidence in critical skills needed for real-world implementation of genome sequencing. Providers reported a significant increase in confidence level in their ability to review, understand, and use genome sequencing result reports to guide patient care. Reported barriers to implementation of genome sequencing in a NICU setting included test cost, lack of insurance coverage, and turn around time. As implementation of genome sequencing in this setting progresses, effective education of NGPs is critical to provide access to high-quality and timely genomic medicine care.

Characteristics and experiences of patients from a community-based and consumer-directed hereditary cancer population screening initiative.

A clinical hereditary cancer population screening initiative, called Information is Power, began in North Alabama in 2015. After 4 years of the initiative, we were interested in exploring (1) the characteristics and motivations for patients who self-refer to population genetic testing, (2) how patients make decisions on testing, (3) what patients do with results, and (4) patient perceptions of benefits and limitations after undergoing population genetic testing. Patients who consented to research recontact at time of test ordering were sent an electronic survey with the option for a follow-up phone interview. Among the 2,918 eligible patients, 239 responded to the survey and 19 completed an interview. Survey and interview participants were highly educated information seekers motivated by learning more about their health. Those who were previously interested in hereditary cancer testing reported barriers were cost and insurance coverage, access to testing, and uncertainty how results could impact their health. Many participants (77%) communicated with family and friends about their decision to test and communicated about test results. Fewer participants (23%) discussed the decision to test with their healthcare providers; however, 58% of participants discussed their test results with a healthcare provider. Most people (96%) with negative results accurately recalled their results. In contrast, three out of 11 positive results for heterozygous MUTYH, PALB2, and BRCA2 reported receiving negative results. This study contributes to knowledge on population genetic testing and may guide other population genetic testing programs as they develop enrollment materials and educational materials and consider downstream needs of population genetic testing participants.

Genome sequencing as a first-line diagnostic test for hospitalized infants.

PURPOSE: SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research. METHODS: GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing. RESULTS: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups. CONCLUSION: We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.

US private payers' perspectives on insurance coverage for genome sequencing versus exome sequencing: A study by the Clinical Sequencing Evidence-Generating Research Consortium (CSER).

PURPOSE: There is limited payer coverage for genome sequencing (GS) relative to exome sequencing (ES) in the U.S. Our objective was to assess payers' considerations for coverage of GS versus coverage of ES and requirements payers have for coverage of GS. The study was conducted by the NIH-funded Clinical Sequencing Evidence-Generating Research Consortium (CSER). METHODS: We conducted semi-structured interviews with representatives of private payer organizations (payers, N = 12) on considerations and evidentiary and other needs for coverage of GS and ES. Data were analyzed using thematic analysis. RESULTS: We described four categories of findings and solutions: demonstrated merits of GS versus ES, enhanced methods for evidence generation, consistent laboratory processes/sequencing methods, and enhanced implementation/care delivery. Payers see advantages to GS vs. ES and are open to broader GS coverage but need more proof of these advantages to consider them in coverage decision-making. Next steps include establishing evidence of benefits in specific clinical scenarios, developing quality standards, ensuring transparency of laboratory methods, developing clinical centers of excellence, and incorporating the role of genetic professionals. CONCLUSION: By comparing coverage considerations for GS and ES, we identified a path forward for coverage of GS. Future research should explicitly address payers' conditions for coverage.

A study of elective genome sequencing and pharmacogenetic testing in an unselected population.

BACKGROUND: Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. METHODS: Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. RESULTS: Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty-four participants (85%) were carriers of a recessive or X-linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. CONCLUSION: Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS.

A review and definition of 'usual care' in genetic counseling trials to standardize use in research.

The descriptor 'usual care' refers to standard or routine care. Yet, no formal definition exists. The need to define what constitutes usual care arises in clinical research. Often one arm in a trial represents usual care in comparison with a novel intervention. Accordingly, usual care in genetic counseling research appears predominantly in randomized controlled trials. Recent standards for reporting genetic counseling research call for standardization, but do not address usual care. We (1) inventoried all seven studies in the Clinical Sequencing Evidence-Generating Consortium (CSER) about how genetic counseling was conceptualized, conducted, and whether a usual care arm was involved; (2) conducted a review of published randomized control trials in genetic counseling, comparing how researchers describe usual care groups; and (3) reviewed existing professionally endorsed definitions and practice descriptions of genetic counseling. We found wide variation in the content and delivery of usual care. Descriptions frequently detailed the content of usual care, most often noting assessment of genetic risk factors, collecting family histories, and offering testing. A minority included addressing psychological concerns or the risks versus benefits of testing. Descriptions of how care was delivered were vague except for mode and type of clinician, which varied. This significant variation, beyond differences expected among subspecialties, reduces the validity and generalizability of genetic counseling research. Ideally, research reflects clinical practice so that evidence generated can be used to improve clinical outcomes. To address this objective, we propose a definition of usual care in genetic counseling research that merges common elements from the National Society of Genetic Counselors' practice definition, the Reciprocal Engagement Model, and the Accreditation Council for Genetic Counselors' practice-based competencies. Promoting consistent execution of usual care in the design of genetic counseling trials can lead to more consistency in representing clinical care and facilitate the generation of evidence to improve it.

Genetic counselor and proxy patient perceptions of genetic counselor responses to prenatal patient self-disclosure requests: Skillfulness is in the eye of the beholder.

Research demonstrates some genetic counselors self-disclose while others do not when patients' request self-disclosure. Limited psychotherapy research suggests skillfulness matters more than type of counselor response. This survey research assessed perceived skillfulness of genetic counselor self-disclosures and non-disclosures. Genetic counselors (n = 147) and proxy patients, women from the public (n = 201), read a hypothetical prenatal genetic counseling scenario and different counselor responses to the patient's question, What would you do if you were me? Participants were randomized either to a self-disclosure study (Study 1) or non-disclosure study (Study 2) and, respectively, rated the skillfulness of five personal disclosures and five professional disclosures or five decline to disclose and five redirecting non-disclosures. Counselor responses in both studies varied by intention (corrective, guiding, interpretive, literal, or reassuring). Participants also described what they thought made a response skillful. A three-way mixed ANOVA in both studies analyzed skillfulness ratings as a function of sample (proxy patient, genetic counselor), response type (personal, professional self-disclosure, or redirecting, declining non-disclosure), and response intention. Both studies found a significant three-way interaction and strong main effect for response intention. Responses rated highest in skillfulness by both genetic counselors and proxy patients in Study 1 were a guiding personal self-disclosure and a personal reassuring self-disclosure. The response rated highest in skillfulness by both samples in Study 2 was a redirecting non-disclosure with a reassuring intention. Proxy patients in both studies rated all literal responses as more skillful than genetic counselors. Participants' commonly described a skillful response as offering guidance and/or reassurance. Counselor intentions and response type appear to influence perceptions, and counselors and patients may not always agree in their perceptions. Consistent with models of practice (e.g., Reciprocal-Engagement Model), genetic counselors generally should aim to convey support and guidance in their responses to prenatal patient self-disclosure requests.

Understanding the present and preparing for the future: Exploring the needs of diagnostic and elective genomic medicine patients.

Advances in genomic knowledge and technology have increased the use of comprehensive clinical sequencing tests. Genome sequencing has established utility for diagnosing patients with rare, undiagnosed diseases as well as interest in an elective context, without a clinical indication for testing. The Smith Family Clinic for Genomic Medicine, LLC in Huntsville, AL is a private practice genomic medicine clinic caring for both diagnostic (79%) and elective (21%) patients. Diagnostic and elective patients are seen on a clinical basis and receive standard care. Genome sequencing is provided on a self-pay basis, with assistance available for diagnostic patients who have financial need. Here, we describe demographics and motivations of the distinct patient populations and our experiences engaging patients in online education. Diagnostic patients were motivated by the possibility of receiving an explanation for symptoms (96%) while elective patients were motivated by the chance to learn about future disease risk (57%). Elective patients were less likely to engage with online education, with only 28% reading all assigned topics compared to 54% of diagnostic patients. Understanding the needs, interests, and barriers unique to diagnostic and elective patients is critical to inform individualized and scalable best practices in patient education and engagement.

Genome-wide association analysis of salinity responsive traits in Medicago truncatula.

Salinity stress is an important cause of crop yield loss in many parts of the world. Here, we performed genome-wide association studies of salinity-stress responsive traits in 132 HapMap genotypes of the model legume Medicago truncatula. Plants grown in soil were subjected to a step-wise increase in NaCl concentration, from 0 through 0.5% and 1.0% to 1.5%, and the following traits were measured: vigor, shoot biomass, shoot water content, leaf chlorophyll content, leaf size, and leaf and root concentrations of proline and major ions (Na+ , Cl- , K+ , Ca2+ , etc.). Genome-wide association studies were carried out using 2.5 million single nucleotide polymorphisms, and 12 genomic regions associated with at least four traits each were identified. Transcript-level analysis of the top eight candidate genes in five extreme genotypes revealed association between salinity tolerance and transcript-level changes for seven of the genes, encoding a vacuolar H+ -ATPase, two transcription factors, two proteins involved in vesicle trafficking, one peroxidase, and a protein of unknown function. Earlier functional studies on putative orthologues of two of the top eight genes (a vacuolar H+ -ATPase and a peroxidase) demonstrated their involvement in plant salinity tolerance.

Phloem Proteomics Reveals New Lipid-Binding Proteins with a Putative Role in Lipid-Mediated Signaling.

Global climate changes inversely affect our ability to grow the food required for an increasing world population. To combat future crop loss due to abiotic stress, we need to understand the signals responsible for changes in plant development and the resulting adaptations, especially the signaling molecules traveling long-distance through the plant phloem. Using a proteomics approach, we had identified several putative lipid-binding proteins in the phloem exudates. Simultaneously, we identified several complex lipids as well as jasmonates. These findings prompted us to propose that phloem (phospho-) lipids could act as long-distance developmental signals in response to abiotic stress, and that they are released, sensed, and moved by phloem lipid-binding proteins (Benning et al., 2012). Indeed, the proteins we identified include lipases that could release a signaling lipid into the phloem, putative receptor components, and proteins that could mediate lipid-movement. To test this possible protein-based lipid-signaling pathway, three of the proteins, which could potentially act in a relay, are characterized here: (I) a putative GDSL-motif lipase (II) a PIG-P-like protein, with a possible receptor-like function; (III) and PLAFP (phloem lipid-associated family protein), a predicted lipid-binding protein of unknown function. Here we show that all three proteins bind lipids, in particular phosphatidic acid (PtdOH), which is known to participate in intracellular stress signaling. Genes encoding these proteins are expressed in the vasculature, a prerequisite for phloem transport. Cellular localization studies show that the proteins are not retained in the endoplasmic reticulum but surround the cell in a spotted pattern that has been previously observed with receptors and plasmodesmatal proteins. Abiotic signals that induce the production of PtdOH also regulate the expression of GDSL-lipase and PLAFP, albeit in opposite patterns. Our findings suggest that while all three proteins are indeed lipid-binding and act in the vasculature possibly in a function related to long-distance signaling, the three proteins do not act in the same but rather in distinct pathways. It also points toward PLAFP as a prime candidate to investigate long-distance lipid signaling in the plant drought response.