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Personalized polygenic risk information may be used to guide risk-based melanoma prevention and early detection at a population scale, but research on communicating this information is limited. This mixed-methods study aimed to assess the acceptability of a genetic counselor (GC) phone call in communicating polygenic risk information in the Melanoma Genomics Managing Your Risk randomized controlled trial. Participants (n = 509) received personalized melanoma polygenic risk information, an educational booklet on melanoma prevention, and a GC phone call, which was audio-recorded. Participants completed the Genetic Counseling Satisfaction Survey 1-month after receiving their risk information (n = 346). A subgroup took part in a qualitative interview post-study completion (n = 20). Survey data were analyzed descriptively using SPSS, and thematic analysis of the qualitative data was conducted using NVivo 12.0 software. The survey showed a high level of acceptability for the GC phone call (mean satisfaction score overall: 4.3 out of 5, standard deviation (SD): 0.6) with differences according to gender (mean score for women: 4.4, SD: 0.6 vs. men: 4.2, SD: 0.7; p = 0.005), health literacy (lower literacy: 4.1, SD: 0.8; average: 4.3, SD: 0.6; higher: 4.4, SD: 0.6: p = 0.02) and polygenic risk group (low risk: 4.5, SD: 0.5, SD: average: 4.3, SD: 0.7, high: 4.3, SD: 0.7; p = 0.03). During the GC phone calls, the discussion predominately related to the impact of past sun exposure on personal melanoma risk. Together our findings point to the importance of further exploring educational and support needs and preferences for communicating personalized melanoma risk among population subgroups, including diverse literacy levels.

Bivariate copula regression allows for the flexible combination of two arbitrary, continuous marginal distributions with regression effects being placed on potentially all parameters of the resulting bivariate joint response distribution. Motivated by the risk factors for adverse birth outcomes, many of which are dichotomous, we consider mixed binary-continuous responses that extend the bivariate continuous framework to the situation where one response variable is discrete (more precisely binary) while the other response remains continuous. Utilizing the latent continuous representation of binary regression models, we implement a penalized likelihood based approach for the resulting class of copula regression models and employ it in the context of modelling gestational age and the presence/absence of low birth weight. The analysis demonstrates the advantage of the flexible specification of regression impacts including nonlinear effects of continuous covariates and spatial effects. Our results imply that racial and spatial inequalities in the risk factors for infant mortality are even greater than previously suggested.

BackgroundCystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediatedCFTRgene therapy formulation through preclinical and clinical development.ObjectiveTo determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF.DesignThis was a randomised, double-blind, placebo-controlled Phase IIb trial of theCFTRgene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers.SettingsData were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database.ParticipantsPatients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination ofCFTRmutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised).InterventionsSubjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year.Main outcome measuresThe primary end point was the relative change in percentage predicted FEV1over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference.ResultsThere was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age orCFTRmutation class. Subjects with a more severe baseline FEV1had a FEV1TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups.ConclusionsMonthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo.LimitationsAlthough encouraging, the improvement in FEV1was modest and was not accompanied by detectable improvement in patients’ quality of life.Future workFuture work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration.Trial registrationClinicalTrials.gov NCT01621867.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.