Risk perception and intended behavior change after uninformative genetic results for adult-onset hereditary conditions in unselected patients.

Population genetic screening for preventable adult-onset hereditary conditions may improve disease management and morbidity but most individuals will receive uninformative results that do not indicate higher risk for disease. Investigation into subsequent psychosocial health and behaviors is necessary to inform population screening feasibility, effectiveness, and cost considerations. We conducted a prospective survey study of unselected University of Washington Medicine patients enrolled in a genetic research study screening for pathogenic variation in medically important genes. Survey questions adapted from the Feelings About genomiC Testing Results (FACToR) questionnaire and designed to understand perceived disease risk change and planned health behaviors were administered after receipt of results. Overall, 2761 people received uninformative results and 1352 (49%) completed survey items. Respondents averaged 41 years old, 62% were female, and 56% were Non-Hispanic Asian. Results from the FACToR instrument showed mean (SD) scores of 0.92 (1.34), 7.63 (3.95), 1.65 (2.23), and 0.77 (1.50) for negative emotions, positive emotions, uncertainty, and privacy concerns, respectively, suggesting minimal psychosocial harms from genetic screening. Overall, 12.2% and 9.6% of survey respondents believed that their risk of cancer or heart disease, respectively, had changed after receiving their uninformative genetic screening results. Further, 8.5% of respondents planned to make healthcare changes and 9.1% other behavior changes. Future work is needed to assess observed behavior changes attributable to uninformative screening results and if small changes in behavior among this population have large downstream impacts.

Dietary magnesium, C-reactive protein and interleukin-6: The Strong Heart Family Study.

OBJECTIVES: To examine the associations of dietary Mg intake with inflammatory biomarkers (C-reactive protein (CRP) and interleukin 6 (IL-6)), and the interaction of dietary Mg intake with single nucleotide polymorphism (SNP) rs3740393, a SNP related to Mg metabolism and transport, on CRP and IL-6 among American Indians (AIs). METHODS: This cross-sectional study included AI participants (n = 1,924) from the Strong Heart Family Study (SHFS). Mg intake from foods and dietary supplements was ascertained using a 119-item Block food frequency questionnaire, CRP and IL-6 were measured from blood, and SNP rs3740393 was genotyped using MetaboChip. Generalized estimating equations were used to examine associations of Mg intake, and the interaction between rs3740393 and dietary Mg, with CRP and IL-6. RESULTS: Reported Mg intake was not associated with CRP or IL-6, irrespective of genotype. A significant interaction (p-interaction = 0.018) was observed between Mg intake and rs3740393 on IL-6. Among participants with the C/C genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.04 (95% CI: -0.10 to 0.17) pg/mL higher. Among participants with the C/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.08 (95% CI: -0.21 to 0.05) pg/mL lower, and among participants with the G/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.19 (95% CI: -0.38 to -0.01) pg/mL lower. CONCLUSIONS: Mg intake may be associated with lower IL-6 with increasing dosage of the G allele at rs3740393. Future research is necessary to replicate this finding and examine other Mg-related genes that influence associations of Mg intake with inflammation.

Factors Influencing Genetic Screening Enrollment among a Diverse, Community-Ascertained Cohort.

INTRODUCTION: Genetic screening for preventable adult-onset hereditary conditions has been proposed as a mechanism to reduce health disparities. Analysis of how race and ethnicity influence decision-making to receive screening can inform recruitment efforts and more equitable population screening design. A study at the University of Washington Medicine that invited unselected patients to participate in genetic screening for pathogenic variation in medically important genes provided an opportunity to evaluate these factors. METHODS: We analyzed screening enrollee survey data to understand factors most important and least important in decision-making about screening overall and across different race and ethnicity groups. Electronic health record race and ethnicity and survey-reported race and ethnicity were compared to assist with interpretation. Comments provided about reasons for not enrolling in screening were analyzed using content analysis. RESULTS: Overall, learning about disease risk and identifying risk early for prevention purposes were important factors in decision-making to receive screening, and regrets about screening and screening being against one's moral code were not viewed as important. Although racial identity was challenging to assign in all cases, compared to other enrollees, African-American and Asian enrollees considered test accuracy and knowing more about the test to be of greater importance. Three themes emerged related to nonparticipation: benefits do not outweigh risks, don't want to know, and challenges with study logistics. CONCLUSION: Our results highlight important motivators for receiving screening and areas that can be addressed to increase screening interest and accessibility. This knowledge can inform future population screening program design including recruitment and education approaches.

Diagnostic yield of genetic screening in a diverse, community-ascertained cohort.

BACKGROUND: Population screening for genetic risk of adult-onset preventable conditions has been proposed as an attractive public health intervention. Screening unselected individuals can identify many individuals who will not be identified through current genetic testing guidelines. METHODS: We sought to evaluate enrollment in and diagnostic yield of population genetic screening in a resource-limited setting among a diverse population. We developed a low-cost, short-read next-generation sequencing panel of 25 genes that had 98.4% sensitivity and 99.98% specificity compared to diagnostic panels. We used email invitations to recruit a diverse cohort of patients in the University of Washington Medical Center system unselected for personal or family history of hereditary disease. Participants were sent a saliva collection kit in the mail with instructions on kit use and return. Results were returned using a secure online portal. Enrollment and diagnostic yield were assessed overall and across race and ethnicity groups. RESULTS: Overall, 40,857 people were invited and 2889 (7.1%) enrolled. Enrollment varied across race and ethnicity groups, with the lowest enrollment among African American individuals (3.3%) and the highest among Multiracial or Other Race individuals (13.0%). Of 2864 enrollees who received screening results, 106 actionable variants were identified in 103 individuals (3.6%). Of those who screened positive, 30.1% already knew about their results from prior genetic testing. The diagnostic yield was 74 new, actionable genetic findings (2.6%). The addition of more recently identified cancer risk genes increased the diagnostic yield of screening. CONCLUSIONS: Population screening can identify additional individuals that could benefit from prevention, but challenges in recruitment and sample collection will reduce actual enrollment and yield. These challenges should not be overlooked in intervention planning or in cost and benefit analysis.

Using species richness calculations to model the global profile of unsampled pathogenic variants: Examples from BRCA1 and BRCA2.

There have been many surveys of genetic variation in BRCA1 and BRCA2 to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate "variant richness" and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenic BRCA1/2 variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety of BRCA1/2 for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate of BRCA1/2 pathogenic variant carriers was 0.64%. BRCA1 c.68_69del is likely the most recurrent BRCA1/2 variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown.