Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

A cross-sectional survey of genetic counselors providing carrier screening regarding GBA variants and Parkinson disease susceptibility.

PURPOSE: Adult-onset disease risks associated with carriers of recessive disease have and will continue to be identified. As carrier screening becomes more broadly utilized, providers face the dilemma of whether they should discuss these risks during discussions with prospective parents. This study aimed to understand whether preconception/prenatal genetic counselors (PPGCs) were aware of the risk of Parkinson disease in carriers of, and persons with, Gaucher disease and the reasons behind choosing whether to discuss this risk with patients. METHODS: Eligible participants included board-certified or board-eligible genetic counselors who had counseled preconception/prenatal patients within the past 3 years. An online survey was distributed via the National Society of Genetic Counselors in November of 2017. RESULTS: One hundred twenty genetic counselors completed the quantitative survey, distributed in Fall of 2017. While the majority of respondents knew of the Gaucher-related Parkinson's link (n = 78; 65%), just over one-third reported discussing it in preconception/prenatal settings (n = 30; 38.5%). Respondents reported discussing these links more consistently when disclosing positive results or when the patient/family approached the topic. Respondents cited the lack of professional guidelines as one of the main reasons for not discussing the link. CONCLUSION: These results highlight an inconsistency in PPGCs' discussions of the Parkinson's risk in Gaucher disease carriers, and the need to develop guidelines regarding these issues to help standardize the care and education of patients.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

What women want: General population perspectives and access to preconception expanded carrier screening.

OBJECTIVE: Expanded carrier screening (ECS) assesses the risk of individuals and couples of having a child affected with a set of genetic conditions. Carriers have options available to optimize pregnancy outcomes based on personal values and preferences. The greatest range of options is available prior to pregnancy, therefore professional societies recommend this screening be performed preconception. This study aimed to assess awareness of, and interest in, ECS in women preconception. Additionally, it aimed to evaluate preferences for timing and location of education and availability of ECS. METHODS: A total of 260 nulliparous women from the general population were surveyed through Qualtrics, a national market research survey platform. Data were delineated using descriptive statistics. RESULTS: Of this cohort, 43.5% reported being aware of ECS prior to the survey and 77.8% indicated interest. Those previously aware were first informed by family, friends, or independent online research. Interest was primarily driven by a desire for reassurance and to make informed decisions about future pregnancies. Interested respondents indicated a willingness to request testing from providers. Participants showed a preference for education and access from a healthcare provider in person. CONCLUSION: These findings provide insight regarding when and where to best educate and reach women prior to pregnancy about ECS to maximize pregnancy outcomes.

Returning negative results from large-scale genomic screening: Experiences from the eMERGE III network.

Population-based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life-altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and "lessons learned" across institutions. A 60-item survey that consisted of both multiple choice and open-ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results.

Comprehension and personal value of negative non-diagnostic genetic panel testing.

Increasing interest and pursuit of genetic testing by the general public have raised concerns about their understanding and use of their results. While most research has focused on individuals receiving positive genetic test results, there have been limited investigations assessing the understanding and utility of receiving negative genetic test results. Individuals who receive a negative (or uninformative) genetic test result may not appreciate the limitations of genetic testing and their residual disease risk. The goals of this study were to explore participant understanding and perceived utility of negative non-diagnostic genetic test results. We conducted semi-structured interviews with participants who received negative non-diagnostic genetic test results from the electronic Medical Records and Genomics Network (eMERGE) testing panel at Northwestern University. A total of 17 participants were interviewed. While many expressed a lack of understanding of genetics and the relationship between genes, disease, and environment, most acknowledged that they had residual risk to develop a health problem and should continue with their routine health management. Additionally, participants expressed that their negative results had personal value, by providing them peace of mind and learning additional knowledge about themselves and their health. Participants did not anticipate that results would have an impact on their lifestyle, but felt the results were useful for sharing with their physician and could inform future genetic testing decisions. While mostly positive, some participants were disappointed not to learn more individualized results. While a more thorough exploration is necessary, findings in this study can aid efforts to improve or innovate informed consent for genomic testing, as well as scalable modes of result return that foster comprehension following negative genetic testing.

Participant choices for return of genomic results in the eMERGE Network.

PURPOSE: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium. METHODS: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices. RESULTS: Across the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes. CONCLUSION: Offering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

Understanding the Return of Genomic Sequencing Results Process: Content Review of Participant Summary Letters in the eMERGE Research Network.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

Parents' attitudes toward consent and data sharing in biobanks: A multisite experimental survey.

BACKGROUND: The factors influencing parents' willingness to enroll their children in biobanks are poorly understood. This study sought to assess parents' willingness to enroll their children, and their perceived benefits, concerns, and information needs under different consent and data-sharing scenarios, and to identify factors associated with willingness. METHODS: This large, experimental survey of patients at the 11 eMERGE Network sites used a disproportionate stratified sampling scheme to enrich the sample with historically underrepresented groups. Participants were randomized to receive one of three consent and data-sharing scenarios. RESULTS: In total, 90,000 surveys were mailed and 13,000 individuals responded (15.8% response rate). 5737 respondents were parents of minor children. Overall, 55% (95% confidence interval 50-59%) of parents were willing to enroll their youngest minor child in a hypothetical biobank; willingness did not differ between consent and data-sharing scenarios. Lower educational attainment, higher religiosity, lower trust, worries about privacy, and attitudes about benefits, concerns, and information needs were independently associated with less willingness to allow their child to participate. Of parents who were willing to participate themselves, 25% were not willing to allow their child to participate. Being willing to participate but not willing to allow one's child to participate was independently associated with multiple factors, including race, lower educational attainment, lower annual household income, public health care insurance, and higher religiosity. CONCLUSIONS: Fifty-five percent of parents were willing to allow their youngest minor child to participate in a hypothetical biobank. Building trust, protecting privacy, and addressing attitudes may increase enrollment and diversity in pediatric biobanks.

What People Want to Know About Their Genes: A Critical Review of the Literature on Large-Scale Genome Sequencing Studies.

From a public health perspective, the "All of Us" study provides an opportunity to isolate targeted and cost-effective prevention and early-detection strategies. Identifying motivations for participation in large-scale genomic sequencing (LSGS) studies, and motivations and preferences to receive results will help determine effective strategies for "All of Us" study implementation. This paper offers a critical review of the literature regarding LSGS for adult onset hereditary conditions where results could indicate an increased risk to develop disease. The purpose of this review is to synthesize studies which explored peoples' motivations for participating in LSGS studies, and their desire to receive different types of genetic results. Participants were primarily motivated by altruism, desire to know more about their health, and curiosity. When asked about hypothetically receiving results, most participants in hypothetical studies wanted all results except those which were uncertain (i.e., a variant of uncertain significance (VUS)). However, participants in studies where results were returned preferred to receive only results for which an intervention was available, but also wanted VUS. Concerns about peoples' understanding of results and possible psychosocial implications are noted. Most studies examined populations classified as "early adopters," therefore, additional research on motivations and expectations among the general public, minority, and underserved populations is needed.

Ethical Considerations Related to Return of Results from Genomic Medicine Projects: The eMERGE Network (Phase III) Experience.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site's research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10-261 days, 0-11, and 11-90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.

Great expectations: patient perspectives and anticipated utility of non-diagnostic genomic-sequencing results.

The management of secondary findings is a challenge to health-care providers relaying clinical genomic-sequencing results to patients. Understanding patients' expectations from non-diagnostic genomic sequencing could help guide this management. This study interviewed 14 individuals enrolled in the eMERGE (Electronic Medical Records and Genomics) study. Participants in eMERGE consent to undergo non-diagnostic genomic sequencing, receive results, and have results returned to their physicians. The interviews assessed expectations and intended use of results. The majority of interviewees were male (64%) and 43% identified as non-Caucasian. A unique theme identified was that many participants expressed uncertainty about the type of diseases they expected to receive results on, what results they wanted to learn about, and how they intended to use results. Participant uncertainty highlights the complex nature of deciding to undergo genomic testing and a deficiency in genomic knowledge. These results could help improve how genomic sequencing and secondary findings are discussed with patients.

The Impact of Family History on the Clinical Features of Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In most cases the disease is inherited from a parent, although a considerable number of affected persons have no reported family history of the disease. While CAG repeat length is negatively correlated with age of symptom onset, variability exists suggesting that other variables may influence symptom onset. OBJECTIVES: The objective of this study is to determine whether awareness of a family history of HD has an impact on symptom onset and disease manifestations. METHODS: Data were obtained from Enroll-HD to compare subjects with a family history of HD to subjects without on various key clinical outcomes. In addition, multiple regressions were performed to investigate the impact of family history on the age at onset of depression and motor symptoms. RESULTS: 4,285 mutation positive subjects were included in the analysis, of which 4.81% had a negative family history. Controlling for CAG repeat length, a positive family history predicted an onset of depression 11.438 years earlier and an onset of motor symptoms 6.681 years earlier when compared to having a negative family history. Subjects with a positive family history were more likely to report behavioral manifestations as the initial major symptom of HD (38.6% vs. 29.6%, p = 0.023), and were more likely to report previous suicidal ideation/attempts (26.2% vs. 20.3%, p = 0.046). CONCLUSIONS: A positive family history of HD appears to be associated with an earlier onset of depression and overall disease manifestations. Implications regarding the role of genetic versus environmental contributions to symptom onset in HD are discussed.

Public Attitudes toward Consent and Data Sharing in Biobank Research: A Large Multi-site Experimental Survey in the US.

Individuals participating in biobanks and other large research projects are increasingly asked to provide broad consent for open-ended research use and widespread sharing of their biosamples and data. We assessed willingness to participate in a biobank using different consent and data sharing models, hypothesizing that willingness would be higher under more restrictive scenarios. Perceived benefits, concerns, and information needs were also assessed. In this experimental survey, individuals from 11 US healthcare systems in the Electronic Medical Records and Genomics (eMERGE) Network were randomly allocated to one of three hypothetical scenarios: tiered consent and controlled data sharing; broad consent and controlled data sharing; or broad consent and open data sharing. Of 82,328 eligible individuals, exactly 13,000 (15.8%) completed the survey. Overall, 66% (95% CI: 63%-69%) of population-weighted respondents stated they would be willing to participate in a biobank; willingness and attitudes did not differ between respondents in the three scenarios. Willingness to participate was associated with self-identified white race, higher educational attainment, lower religiosity, perceiving more research benefits, fewer concerns, and fewer information needs. Most (86%, CI: 84%-87%) participants would want to know what would happen if a researcher misused their health information; fewer (51%, CI: 47%-55%) would worry about their privacy. The concern that the use of broad consent and open data sharing could adversely affect participant recruitment is not supported by these findings. Addressing potential participants' concerns and information needs and building trust and relationships with communities may increase acceptance of broad consent and wide data sharing in biobank research.

Conducting a large, multi-site survey about patients' views on broad consent: challenges and solutions.

BACKGROUND: As biobanks play an increasing role in the genomic research that will lead to precision medicine, input from diverse and large populations of patients in a variety of health care settings will be important in order to successfully carry out such studies. One important topic is participants' views towards consent and data sharing, especially since the 2011 Advanced Notice of Proposed Rulemaking (ANPRM), and subsequently the 2015 Notice of Proposed Rulemaking (NPRM) were issued by the Department of Health and Human Services (HHS) and Office of Science and Technology Policy (OSTP). These notices required that participants consent to research uses of their de-identified tissue samples and most clinical data, and allowing such consent be obtained in a one-time, open-ended or "broad" fashion. Conducting a survey across multiple sites provides clear advantages to either a single site survey or using a large online database, and is a potentially powerful way of understanding the views of diverse populations on this topic. METHODS: A workgroup of the Electronic Medical Records and Genomics (eMERGE) Network, a national consortium of 9 sites (13 separate institutions, 11 clinical centers) supported by the National Human Genome Research Institute (NHGRI) that combines DNA biorepositories with electronic medical record (EMR) systems for large-scale genetic research, conducted a survey to understand patients' views on consent, sample and data sharing for future research, biobank governance, data protection, and return of research results. RESULTS: Working across 9 sites to design and conduct a national survey presented challenges in organization, meeting human subjects guidelines at each institution, and survey development and implementation. The challenges were met through a committee structure to address each aspect of the project with representatives from all sites. Each committee's output was integrated into the overall survey plan. A number of site-specific issues were successfully managed allowing the survey to be developed and implemented uniformly across 11 clinical centers. CONCLUSIONS: Conducting a survey across a number of institutions with different cultures and practices is a methodological and logistical challenge. With a clear infrastructure, collaborative attitudes, excellent lines of communication, and the right expertise, this can be accomplished successfully.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

rs4771122 Predicts Multiple Measures of Long-Term Weight Loss After Bariatric Surgery.

We examined the association of 34 single nucleotide polymorphisms with weight loss up to 9.5 years after Roux-en-Y surgery. Participants were enrollees in the NUgene biobank with stored DNA and linked electronic health records. Ninety-five self-identified white participants underwent surgery and had follow-up weights obtained between 1 and 9.5 years after surgery. SNP rs4771122 was the variant most significantly associated with long-term weight loss after surgery in a repeated linear mixed model (p = .004) of long-term weight loss. In this model, each additional copy of the minor allele was associated with nearly 5 % greater percentage weight loss. This same SNP was also nominally significantly (p < .05) associated with weight loss trajectories, weight loss nadir, and weight loss 2 years after surgery.

Factors Associated With Long-Term Weight Loss Following Bariatric Surgery Using 2 Methods for Repeated Measures Analysis.

We used electronic health record data from 162 patients enrolled in the NUgene Project (2002-2013) to determine demographic factors associated with long-term (from 1 to up to 9.5 (mean = 5.6) years) weight loss following Roux-en-Y gastric bypass surgery. Ninety-nine (61.1%) patients self-reported white, and 63 (38.9%) self-reported black, mixed, or missing race. The average percent weight loss was -33.4% (standard deviation, 9.3) at 1 year after surgery and -30.7% (standard deviation, 12.5) at the last follow-up point. We used linear mixed and semiparametric trajectory models to test the association of surgical and demographic factors (height, surgery age, surgery weight, surgery body mass index, marital status, sex, educational level, site, International Classification of Diseases code, Current Procedural Terminology code, Hispanic ethnicity, and self-reported race) with long-term percent weight loss and pattern of weight loss. We found that black, mixed, and missing races (combined) in comparison with white race were associated with a decreased percent weight loss of -4.31% (95% confidence interval: -7.30, -1.32) and were less likely to have higher and sustained percent weight loss (P = 0.04). We also found that less obese patients were less likely to have higher and sustained percent weight loss (P = 0.01). These findings may be helpful to patients in setting expectations after weight loss surgery.