Background: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.

No abstract

See Editorial by Aguilar

Background Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase healthcare utilization without clinical value. Objective Describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design Pilot randomized trial. Setting Academic primary care practices. Participants Nine primary care physicians (PCPs) and 100 generally healthy patients aged 40–65. Interventions Patients were randomly assigned to receive a family history report alone (FH arm) or in combination with an interpreted WGS report including monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits (FH+WGS arm). Each patient met with his or her PCP to discuss the reports. Measurements Clinical outcomes and healthcare utilization through six months were obtained from audio-recorded PCP-patient discussions and medical records. Patients’ health behavior changes were surveyed six months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results. Results Mean age was 55 years; 58% were female. Eleven FH+WGS patients (22%, 12%–36%) had new MDR results. Only two (4%, 0.01%–14%) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). PCPs recommended new clinical actions for 16% (8%–30%) of FH patients and 34% (22%–49%) of FH+WGS patients. Thirty (17%–45%) and 41% (27%–56%) of FH and FH+WGS patients, respectively, reported making a health behavior change after six months. Geneticists rated PCP management of eight MDR results (73%, 39%–99%) as appropriate and two (18%, 3%–52%) as inappropriate. Limitations Limited sample size and ancestral and socioeconomic diversity. Conclusions Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Non-geneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value. Registration ClinicalTrials.gov identifier NCT01736566 Funding National Institutes of Health

OBJECTIVETo examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors.RESEARCH DESIGN AND METHODSWe conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants.RESULTSThe 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m2, with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison).CONCLUSIONSDiabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes.

Genome-wide association studies (GWAS) may have reached their limit of detecting common type 2 diabetes (T2D)–associated genetic variation. We evaluated the performance of current polygenic T2D prediction. Using data from the Framingham Offspring (FOS) and the Coronary Artery Risk Development in Young Adults (CARDIA) studies, we tested three hypotheses: 1) a 62-locus genotype risk score (GRSt) improves T2D prediction compared with previous less inclusive GRSt; 2) separate GRS for β-cell (GRSβ) and insulin resistance (GRSIR) independently predict T2D; and 3) the relationships between T2D and GRSt, GRSβ, or GRSIR do not differ between blacks and whites. Among 1,650 young white adults in CARDIA, 820 young black adults in CARDIA, and 3,471 white middle-aged adults in FOS, cumulative T2D incidence was 5.9%, 14.4%, and 12.9%, respectively, over 25 years. The 62-locus GRSt was significantly associated with incident T2D in all three groups. In FOS but not CARDIA, the 62-locus GRSt improved the model C statistic (0.698 and 0.726 for models without and with GRSt, respectively; P < 0.001) but did not materially improve risk reclassification in either study. Results were similar among blacks compared with whites. The GRSβ but not GRSIR predicted incident T2D among FOS and CARDIA whites. At the end of the era of common variant discovery for T2D, polygenic scores can predict T2D in whites and blacks but do not outperform clinical models. Further optimization of polygenic prediction may require novel analytic methods, including less common as well as functional variants.

National Human Genome Research Institute, Doris Duke Charitable Foundation, National Health Service Blood and Transplant, National Institute for Health Research, and Wellcome Trust.

BackgroundWhole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care.Methods/DesignThis pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients’ genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results.DiscussionThe impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies.Trial registrationClinicalTrials.gov identifier NCT01736566