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Background Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Under-recognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. Research Question The study addressed three questions: 1) Does a DTC testing service identify previously undetected individuals with AATD? 2) What was the time interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and 3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? Study Design and Methods In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. Results Among 195,014 study participants, the allele frequency for either the PI*S and PI*Z AATD variants was 21.6% (6.5% for PI*Z and 15.1% for PI*S); 0.63% were PI*ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly-aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with healthcare providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI*ZZ individuals shared their DTC result with an HCP. The odds ratio for PI*ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 [CI 1.4, 2.2] compared to those without a Z allele and for reduced alcohol consumption was 4.0 [CI 2.6, 5.9]. Interpretation In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

Author(s): Kaplan, Celia P; Siegel, Adam; Leykin, Yan; Palmer, Nynikka R; Borno, Hala; Bielenberg, Jessica; Livaudais-Toman, Jennifer; Ryan, Charles; Small, Eric J | Abstract: BackgroundTo address limitations in recruitment and enrollment of diverse, low-literacy patients into prostate cancer clinical trials, we evaluated the feasibility, acceptability, and efficacy of an English and Spanish, Internet-based, multilevel recruitment intervention.MethodsIntervention components included (1) a low-literacy, bilingual, automated, Internet-based clinical trial matching tool; (2) a bilingual nurse who assisted individuals with questions and enrollment; and (3) a targeted, Internet-based advertising campaign. We evaluated (a) completion of matching tool, (b) expression of interest in a clinical trial, (c) number of patients who matched to clinical trials at a single institution, (d) discussion of risks and benefits of clinical trials (via follow-up interviews), and (e) effect of the advertising on completing the matching tool. Feasibility, acceptability, and preliminary estimates of efficacy were measured through user engagement with the matching tool and subsequent qualitative interviews with these same users.ResultsDuring the 28-week study period, 523 users provided demographic information, 263 were identified with prostate cancer, 192 (73%) matched to at least one clinical trial, and 29 (15.1%) of those who matched provided contact information. During the study period, 17 prostate cancer clinical trials were available for matching. We completed follow-up interviews with 14 of the 29 men who provided contact information. Of the 14, 85.7% discussed the risks and benefits of clinical trials with their physician, and 35.7% enrolled in a clinical trial. The Internet-based advertising campaign resulted in an increased number of matching tool completions.ConclusionsOur study demonstrates that an Internet-based clinical trial matching tool that is advertised using a targeted Internet-based campaign can provide an effective means to reach diverse, low-literacy patients. When implemented at scale and over a longer duration, such interventions may help increase trial participation among underrepresented populations.