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Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Background: Pediatric obesity is characterized by an imbalance in pro- and anti-inflammatory markers that are associated with cardiometabolic diseases. Adiponectin (Adpn), an anti-inflammatory marker, is associated with insulin sensitivity, while tumor necrosis factor-alpha (TNFα) has been associated with insulin resistance among youth with obesity. However, it is unknown whether longitudinal changes in Adpn or TNFα predict changes in insulin sensitivity among high-risk youth. Methods: A total of 73 Latino youth with obesity (age 13.3±1.4 y, Female 40.3%, BMIz 2.2±0.3) were enrolled in either a lifestyle intervention or usual care. Given that there were no between-group differences in changes in insulin sensitivity at 6-months, groups were combined for the present analysis. Fasting serum samples were used to measure high-molecular weight Adpn and TNFα before and after intervention. Insulin sensitivity was estimated by the whole-body insulin sensitivity index (WBISI) using insulin and glucose concentrations from a 75-g, 2-h oral glucose tolerance test. Baseline associations were analyzed using Pearson correlations. Linear regression was used to analyze whether changes in Adpn or TNFα predict changes in WBISI, adjusting for age, sex, and intervention assignment. Data from linear regressions are presented as betas (β) and standard errors (SE). Results: At baseline, WBISI was positively and significantly associated with Adpn (r=0.296, p=0.015) but not with TNFα (r=-0.171, p=0.168), adjusting for age and sex. Increases in Adpn were associated with increases in WBISI, whereby for every 1 μg/dL increase in Adpn, there was a 0.7 unit increase in WBISI (SE=0.3, p=0.027). Changes in TNFα did not significantly predict changes in WBISI (β=0.1, SE=0.5, p=0.915). Conclusion: Changes in Adpn but not TNFα were associated with changes in insulin sensitivity following intervention among Latino youth with obesity. Whether Adpn is the mechanism by which health behavior changes increase insulin sensitivity warrants further investigation among high-risk youth populations.

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.

Summary Single-minded homolog 1 (SIM1) is a transcription factor that plays a role in the development of both the hypothalamus and pituitary. SIM1 gene mutations are known to cause obesity in humans, and chromosomal deletions encompassing SIM1 and other genes necessary for pituitary development can cause a Prader–Willi-like syndrome with obesity and hypopituitarism. There have been no reported cases of hypopituitarism linked to a single SIM1 mutation. A 21-month-old male presented to endocrinology clinic with excessive weight gain and severe obesity. History was also notable for excessive drinking and urination. Endocrine workup revealed central hypothyroidism, partial diabetes insipidus, and central adrenal insufficiency. Genetic evaluation revealed a novel mutation in the SIM1 gene. No other genetic abnormalities to account for his obesity and hypopituitarism were identified. While we cannot definitively state this mutation is pathogenic, it is notable that SIM1 plays a role in the development of all three of the patient’s affected hormone axes. He is now 6 years old and remains on treatment for his pituitary hormone deficiencies and continues to exhibit excessive weight gain despite lifestyle interventions. Learning points: Mutations in SIM1 are a well-recognized cause of monogenic human obesity, and there have been case reports of Prader–Willi-like syndrome and hypopituitarism in patients with chromosomal deletions that contain the SIM1 gene. SIM1 is expressed during the development of the hypothalamus, specifically in neuroendocrine lineages that give rise to the hormones oxytocin, arginine vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin. Pituitary testing should be considered in patients with severe obesity and a known genetic abnormality affecting the SIM1 gene, particularly in the pediatric population.

Although obesity and mental health disorders are two major public health problems in adolescents that affect academic performance, few rigorously designed experimental studies have been conducted in high schools.The goal of the study was to test the efficacy of the COPE (Creating Opportunities for Personal Empowerment) Healthy Lifestyles TEEN (Thinking, Emotions, Exercise, Nutrition) Program, versus an attention control program (Healthy Teens) on: healthy lifestyle behaviors, BMI, mental health, social skills, and academic performance of high school adolescents immediately after and at 6 months post-intervention.A cluster RCT was conducted. Data were collected from January 2010 to May of 2012 and analyzed in 2012-2013.A total of 779 culturally diverse adolescents in the U.S. Southwest participated in the trial.COPE was a cognitive-behavioral skills-building intervention with 20 minutes of physical activity integrated into a health course, taught by teachers once a week for 15 weeks. The attention control program was a 15-session, 15-week program that covered common health topics.Primary outcomes assessed immediately after and 6 months post-intervention were healthy lifestyle behaviors and BMI. Secondary outcomes included mental health, alcohol and drug use, social skills, and academic performance.Post-intervention, COPE teens had a greater number of steps per day (p=0.03) and a lower BMI (p=0.01) than did those in Healthy Teens, and higher average scores on all Social Skills Rating System subscales (p-values0.05). Teens in the COPE group with extremely elevated depression scores at pre-intervention had significantly lower depression scores than the Healthy Teens group (p=0.02). Alcohol use was 12.96% in the COPE group and 19.94% in the Healthy Teens group (p=0.04). COPE teens had higher health course grades than did control teens. At 6 months post-intervention, COPE teens had a lower mean BMI than teens in Healthy Teens (COPE=24.72, Healthy Teens=25.05, adjusted M=-0.34, 95% CI=-0.56, -0.11). The proportion of those overweight was significantly different from pre-intervention to 6-month follow-up (chi-square=4.69, p=0.03), with COPE decreasing the proportion of overweight teens, versus an increase in overweight in control adolescents. There also was a trend for COPE Teens to report less alcohol use at 6 months (p=0.06).COPE can improve short- and more long-term outcomes in high school teens.This study is registered at www.clinicaltrials.gov NCT01704768.