Severe Hypoglycemia and the Use of Glucagon Rescue Agents: An Observational Survey in Adults With Type 1 Diabetes.

Severe hypoglycemia (SH) is the most frequent and potentially serious complication affecting individuals with type 1 diabetes and can have major clinical and psychosocial consequences. Glucagon is the only approved treatment for SH that can be administered by non-health care professionals (HCPs); however, reports on the experiences and emotions of people with type 1 diabetes associated with SH and glucagon rescue use are limited. This survey study demonstrated that an increasing number of individuals with type 1 diabetes have current and filled prescriptions for glucagon and have been educated about glucagon rescue use by an HCP. Despite this positive trend, challenges with SH remain, including a high level of health care resource utilization, considerable out-of-pocket expenses for glucagon kits, a high prevalence of hypoglycemia unawareness, and a negative emotional impact on individuals with diabetes. Nocturnal and exercise-related hypoglycemia were concerns for most survey participants.

Emergency Glucagon: a Focused Review of Psychosocial Experiences of Rescue Drugs for Type 1 Diabetes.

PURPOSE OF REVIEW: The purpose of this paper is to describe rescue glucagon types, safety, efficacy, and preferences, as well as to review articles regarding emergency glucagon usage, severe hypoglycemia, and the emotions of both phenomena. We conducted a review of current literature on glucagon usage and the emotional impact of severe hypoglycemia on people with diabetes (PwD) and the caregivers of people with type 1 diabetes (T1D). RECENT FINDINGS: Minimal research exists pertaining to glucagon and severe hypoglycemic experiences in PwD, which is troubling considering the severity of risks and possible side effects. Recent articles described negative emotions such as fear, anxiety, stress, helplessness, shame, embarrassment, loneliness, frustration, hopefulness, and uncertainty surrounding glucagon usage. There is scarce research regarding PwD's emotions surrounding severe hypoglycemia and rescue glucagon use. Additional research is needed to investigate the emotions and feelings people with T1D and their caregivers' experience pertaining to severe hypoglycemia and emergency glucagon use.

Return of genomic results to research participants: the floor, the ceiling, and the choices in between.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.

Ethical and practical challenges of sharing data from genome-wide association studies: the eMERGE Consortium experience.

In 2007, the National Human Genome Research Institute (NHGRI) established the Electronic MEdical Records and GEnomics (eMERGE) Consortium (www.gwas.net) to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic medical record (EMR) systems for large-scale, high-throughput genetic research. One of the major ethical and administrative challenges for the eMERGE Consortium has been complying with existing data-sharing policies. This paper discusses the challenges of sharing genomic data linked to health information in the electronic medical record (EMR) and explores the issues as they relate to sharing both within a large consortium and in compliance with the National Institutes of Health (NIH) data-sharing policy. We use the eMERGE Consortium experience to explore data-sharing challenges from the perspective of multiple stakeholders (i.e., research participants, investigators, and research institutions), provide recommendations for researchers and institutions, and call for clearer guidance from the NIH regarding ethical implementation of its data-sharing policy.

Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.

PURPOSE: Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). METHODS: In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. RESULTS: We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. CONCLUSIONS: This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.

Generalization of variants identified by genome-wide association studies for electrocardiographic traits in African Americans.

Electrocardiographic (ECG) measurements vary by ancestry. Genome-wide association studies (GWAS) have identified loci that contribute to ECG measurements; however, most are performed in Europeans collected from population-based cohorts or surveys. The strongest associations reported are in NOS1AP with QT interval and SCN10A with PR and QRS durations. The extent to which these associations can be generalized to African Americans has yet to be determined. Using electronic medical records, PR and QT intervals, QRS duration, and heart rate were determined in 455 African Americans as part of the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project. We tested for an association between these ECG traits and >930K SNPs. We identified a total 36 novel associations with PR interval, QRS duration, QT interval, and heart rate at p < 1.0 × 10(-6). Using published GWAS data, we compared our results with those previously identified in other populations. Five associations originally identified in other populations generalized with respect to statistical significance and direction of effect. A total of 43 associations have a consistent direction of effect with European and/or Asian populations. This work provides a catalogue of generalized versus nongeneralized associations, a necessary step in prioritizing GWAS-identified regions for further fine-mapping in diverse populations.

Emerging Adult and Caregiver Psychosocial Experiences with Severe Hypoglycemic Events and the Perceived Impact of Nasal Glucagon: A Cross-Sectional Study.

INTRODUCTION: Severe hypoglycemic events are distressing. Although past studies have shown that young adulthood is a potentially distressing time, few studies have explored distress about severe hypoglycemia in this age group. The real-world psychosocial experiences of potential severe hypoglycemic events and the perceived impact of glucagon treatments like nasal glucagon are currently unknown. We explored perceptions of severe hypoglycemic events and impact of nasal glucagon on psychosocial experiences with these events in emerging adults with type 1 diabetes and caregivers of emerging adults and children/teens. Further, we compared perceptions of preparedness and protection in handling severe hypoglycemic events with nasal glucagon versus the emergency glucagon kit that requires reconstitution (e-kit). METHODS: This observational, cross-sectional study enrolled emerging adults (aged 18-26; N = 364) with type 1 diabetes, caregivers of emerging adults (aged 18-26; N = 138) with type 1 diabetes, and caregivers of children/teens (aged 4-17; N = 315) with type 1 diabetes. Participants completed an online survey about their experiences with severe hypoglycemia, perceptions of nasal glucagon impact on psychosocial experiences, and perceptions of feeling prepared and protected with nasal glucagon and the e-kit. RESULTS: Many emerging adults (63.7%) agreed that the experience of severe hypoglycemic events was distressing; 33.3% and 46.7% of caregivers of emerging adults and children/teens, respectively, reported distress. Participants reported positive perceptions of nasal glucagon impact, particularly improved confidence in other people's ability to help during severe hypoglycemic events: emerging adults, 81.4%; caregivers of emerging adults, 77.6%; caregivers of children/teens, 75.5%. Participants demonstrated higher perceptions of preparedness and protection for nasal glucagon than for the e-kit (p < 0.001). CONCLUSIONS: Participants reported improved confidence in other people's ability to help during severe hypoglycemic events since having nasal glucagon available. This suggests that nasal glucagon may help broaden the support network for young people with type 1 diabetes and their caregivers.

Prevalence of fear of hypoglycemia in adults with type 1 diabetes using a newly developed screener and clinician's perspective on its implementation.

INTRODUCTION: Fear of hypoglycemia (FoH) affects quality of life, emotional well-being, and diabetes management among people with type 1 diabetes (PwT1D). American Diabetes Association's (ADA) guidelines recommend assessing FoH in clinical practice. However, existing FoH measures are commonly used in research and not in clinical practice. In this study, prevalence of FoH was assessed in PwT1D using a newly developed FoH screener for clinical practice; its association with established measures and outcomes was also determined. In addition, healthcare providers' (HCPs) perspectives on implementing FoH screener into real-world practice were explored. RESEARCH DESIGN AND METHODS: This multiphase observational study used mixed methods in two phases. First, we collected a cross-sectional survey (including the screener) from PwT1D (≥18 years) from T1D Exchange Quality Improvement Collaborative adult clinics. Pearson correlations and regression analyses were performed on diabetes outcome measures using screener scores. Second, we conducted focus groups among HCPs who treat PwT1D and descriptive analysis to summarize results. RESULTS: We included 553 PwT1D. Participants had a mean±SD age of 38.9±14.2 years and 30% reported a high FoH total score. Regression analyses showed that higher A1c and higher number of comorbidities were significantly associated with high FoH (p<0.001). High FoH worry and behavior scores were significantly associated with 8-Item Patient Health Questionnaire and 7-Item Generalized Anxiety Disorder Scale scores. Participants with ≥1 severe hypoglycemia event(s) and impaired awareness of hypoglycemia had higher odds of high FoH. Eleven HCPs participated in focus group interviews; they expressed that the FoH screener is clinically necessary and relevant but poses implementation challenges that must be addressed. CONCLUSIONS: Our results demonstrate FoH is common in PwT1D and affects their psychosocial well-being and diabetes management. In alignment with ADA position statement, HCP focus group results emphasize importance of screening for FoH. Implementing this newly developed FoH screener may help HCPs identify FoH in PwT1D.

Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network.

PURPOSE: Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors. METHODS: The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making. RESULTS: Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site). CONCLUSION: The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.

Managing incidental findings and research results in genomic research involving biobanks and archived data sets.

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using "biobank" here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.

Nonmuscle myosin IIA with a GFP fused to the N-terminus of the regulatory light chain is regulated normally.

Nonmuscle myosin II plays a crucial role in a variety of cellular processes (e.g., polarity formation, cell motility, and cytokinesis). It is composed of two heavy chains, two regulatory light chains and two essential light chains. The ATPase activity of the myosin II motor domain is regulated through phosphorylation of the regulatory light chain (RLC) by myosin light chain kinase. To study myosin function and localization in cellular processes, GFP-fused RLCs are widely used; however, the exact kinetic properties of myosins with bound GFP-RLC are poorly described. More importantly, it has not been shown that a regulatory light chain fused at its N-terminus with GFP can maintain the normal phosphorylation-dependent regulation of nonmuscle myosin or serve as a substrate for myosin light chain kinase. We coexpressed N-terminal GFP-RLC with a heavy meromyosin (HMM)-like fragment of nonmuscle myosin IIA and essential light chain to characterize the phosphorylation dynamics and in vitro kinetic properties of the resulting HMM. Myosin light chain kinase phosphorylates the GFP-RLC bound to HMM IIA with the same V(max) as it does the wild type RLC bound to HMM IIA, but the K(m) is about two fold higher for the GFP fusion protein, meaning that it is a somewhat poorer substrate. The steady-state actin-activated MgATPase activity of the GFP-RLC HMM is very low in the absence of phosphorylation demonstrating that the GFP moiety does not prevent formation of the off state. The actin-activated MgATPase activity of phosphorylated GFP-RLC-HMM and is about half that of wild type phosphorylated HMM. The ability of phosphorylated GFP-RLC-HMM to move actin filaments in the actin gliding assay is also slightly compromised. These data indicate that despite some kinetic differences the N-terminal GFP fusion to the regulatory light chain is a reasonable model system for studying myosin function in vivo.

Sensitive detection of multiple islet autoantibodies in type 1 diabetes using small sample volumes by agglutination-PCR.

Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. However, the reliance on radioactive components, large sample volumes and limited throughput renders radioassay testing costly and challenging. We developed a multiplex analysis platform based on antibody detection by agglutination-PCR (ADAP) for the sample-sparing measurement of GAD, IA-2 and insulin autoantibodies/antibodies in 1 µL serum. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. Measurements from the ADAP assay were compared to radioassay to determine correlation, concordance, agreement, clinical sensitivity and specificity. The average overall agreement between ADAP and radioassay was above 91%. The average clinical sensitivity and specificity were 96% and 97%. In the IASP 2018 workshop, ADAP achieved the highest sensitivity of all assays tested at 95% specificity (AS95) rating for GAD and IA-2 autoantibodies and top-tier performance for insulin autoantibodies. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1µL serum with high sensitivity. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies.

A fluorescent resonant energy transfer-based biosensor reveals transient and regional myosin light chain kinase activation in lamella and cleavage furrows.

Approaches with high spatial and temporal resolution are required to understand the regulation of nonmuscle myosin II in vivo. Using fluorescence resonance energy transfer we have produced a novel biosensor allowing simultaneous determination of myosin light chain kinase (MLCK) localization and its [Ca2+]4/calmodulin-binding state in living cells. We observe transient recruitment of diffuse MLCK to stress fibers and its in situ activation before contraction. MLCK is highly active in the lamella of migrating cells, but not at the retracting tail. This unexpected result highlights a potential role for MLCK-mediated myosin contractility in the lamella as a driving force for migration. During cytokinesis, MLCK was enriched at the spindle equator during late metaphase, and was maximally activated just before cleavage furrow constriction. As furrow contraction was completed, active MLCK was redistributed to the poles of the daughter cells. These results show MLCK is a myosin regulator in the lamella and contractile ring, and pinpoints sites where myosin function may be mediated by other kinases.

Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration - experience from a pediatric tertiary care facility.

OBJECTIVE: This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR). MATERIALS AND METHODS: An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy. RESULTS: Clinical decision support rules built within an EHR provided guidance to providers for 31 patients (100%) who had actionable PGx variants and were written for interacting medications. A breakdown of the PGx alerts by practitioner service, and alert response for the initial cohort of patients tested is described. In 90% (355/394) of the cases, thiopurine methyltranferase genotyping was ordered pre-emptively. DISCUSSION: This paper outlines one approach to implementing a clinical PGx service in a pediatric teaching hospital that cares for a heterogeneous patient population. There is a focus on incorporation of PGx clinical decision support rules and a program to standardize report text within the electronic health record with subsequent exploration of clinician behavior in response to the alerts. CONCLUSION: The incorporation of PGx data at the time of prescribing and dispensing, if done correctly, has the potential to impact the incidence of adverse drug events, a significant cause of morbidity and mortality.

Healthcare provider education to support integration of pharmacogenomics in practice: the eMERGE Network experience.

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study.

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

Practical considerations for implementing genomic information resources. Experiences from eMERGE and CSER.

OBJECTIVES: To understand opinions and perceptions on the state of information resources specifically targeted to genomics, and approaches to delivery in clinical practice. METHODS: We conducted a survey of genomic content use and its clinical delivery from representatives across eight institutions in the electronic Medical Records and Genomics (eMERGE) network and two institutions in the Clinical Sequencing Exploratory Research (CSER) consortium in 2014. RESULTS: Eleven responses representing distinct projects across ten sites showed heterogeneity in how content is being delivered, with provider-facing content primarily delivered via the electronic health record (EHR) (n=10), and paper/pamphlets as the leading mode for patient-facing content (n=9). There was general agreement (91%) that new content is needed for patients and providers specific to genomics, and that while aspects of this content could be shared across institutions there remain site-specific needs (73% in agreement). CONCLUSION: This work identifies a need for the improved access to and expansion of information resources to support genomic medicine, and opportunities for content developers and EHR vendors to partner with institutions to develop needed resources, and streamline their use - such as a central content site in multiple modalities while implementing approaches to allow for site-specific customization.

Admixture mapping and subsequent fine-mapping suggests a biologically relevant and novel association on chromosome 11 for type 2 diabetes in African Americans.

Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10(-8) by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.