ObjectivesA survey of a population-based sample of U.S adults was conducted to measure their attitudes about, and inform the design of the Precision Medicine Initiative’s planned national cohort study.MethodsAn online survey was conducted by GfK between May and June of 2015. The influence of different consent models on willingness to share data was examined by randomizing participants to one of eight consent scenarios.ResultsOf 4,777 people invited to take the survey, 2,706 responded and 2,601 (54% response rate) provided valid responses. Most respondents (79%) supported the proposed study, and 54% said they would definitely or probably participate if asked. Support for and willingness to participate in the study varied little among demographic groups; younger respondents, LGBT respondents, and those with more years of education were significantly more likely to take part if asked. The most important study incentive that the survey asked about was learning about one’s own health information. Willingness to share data and samples under broad, study-by-study, menu and dynamic consent models was similar when a statement about transparency was included in the consent scenarios. Respondents were generally interested in taking part in several governance functions of the cohort study.ConclusionsA large majority of the U.S. adults who responded to the survey supported a large national cohort study. Levels of support for the study and willingness to participate were both consistent across most demographic groups. The opportunity to learn health information about one’s self from the study appears to be a strong motivation to participate.

Summary Context Morphological characteristics of the glucose curve during an OGTT (time to peak and shape) may reflect different phenotypes of insulin secretion and action, but their ability to predict diabetes risk is uncertain. Objective To compare the ability of time to glucose peak and curve shape to detect prediabetes and β-cell function. Design and participants In a cross-sectional evaluation using an OGTT, 145 adults without diabetes (age 42±9y (mean±SD), range 24–62y, BMI 29.2±5.3 kg/m2, range 19.9–45.2 kg/m2) were characterized by peak (30 mins vs. >30 mins) and shape (biphasic vs. monophasic). Main Outcome Measures Prediabetes and disposition index (DI) – a marker of β-cell function. Results Prediabetes was diagnosed in 36% (52/145) of participants. Peak >30 mins, not monophasic curve, was associated with increased odds of prediabetes (OR: 4.0 vs. 1.1; P<0.001). Both monophasic curve and peak >30 mins were associated with lower DI (P≤0.01). Time to glucose peak and glucose AUC were independent predictors of DI (adjR2=0.45, P<0.001) Conclusion Glucose peak >30 mins was a stronger independent indicator of prediabetes and β-cell function than the monophasic curve. Time to glucose peak may be an important tool that could enhance prediabetes risk stratification.

Purpose Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients. Methods Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients. Results Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection. Conclusion Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.