Citations

Abstract Background For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes ( BRCA1, BRCA2, PALB2, ATM, CHEK2 ). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion This flexible, variant-level methodology combines nationally-collected ‘enriched’ datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.

Abstract Background: Increasing colorectal cancer screening (CRCS) is important for attaining the Healthy People 2020 goal of reducing CRC-related morbidity and mortality. Evaluating CRCS trends can help identify shifts in CRCS, and specific groups that might be targeted for CRCS. Methods: We utilized medical records to describe population-based adherence to average-risk CRCS guidelines from 1997 to 2008 in Olmsted County, MN. CRCS trends were analyzed overall and by gender, age, and adherence to screening mammography (women only). We also carried out an analysis to examine whether CRCS is being initiated at the recommended age of 50. Results: From 1997 to 2008, the size of the total eligible sample ranged from 20,585 to 21,468 people. CRCS increased from 22% to 65% for women and from 17% to 59% for men (P < 0.001 for both) between 1997 and 2008. CRCS among women current with mammography screening increased from 26% to 74%, and this group was more likely to be adherent to CRCS than all other subgroups analyzed (P < 0.001).The mean ages of screening initiation were stable throughout the study period, with a mean age of 55 years among both men and women in 2008. Conclusion: Although overall CRCS tripled during the study period, there is still room for improvement. Impact: Working to decrease the age at first screening, exploration of gender differences in screening behavior, and targeting women adherent to mammography but not to CRCS seem warranted. Cancer Epidemiol Biomarkers Prev; 21(2); 347–50. ©2011 AACR.