Citations

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Previous genome‐wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine‐mapping study across 2.06 Mb (chr8:127,561,724–129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93–0.97, conditional p = 5.8 × 10−6), rs7815245 (OR = 0.94, 95% CI = 0.91–0.96, conditional p = 1.1 × 10−6) and rs2033101 (OR = 1.05, 95% CI = 1.02–1.07, conditional p = 1.1 × 10−4) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Abstract Objective: Hypoparathyroidism is a rare disorder characterized by hypocalcemia and absent or deficient PTH. This report presents a summary of current information about epidemiology, presentation, diagnosis, clinical features, and management and proposes guidelines to help clinicians diagnose, evaluate, and manage this disorder. Participants: Participants in the First International Conference on the Management of Hypoparathyroidism represented a worldwide constituency with acknowledged interest and expertise in key basic, translational, and clinical aspects of hypoparathyroidism. Three Workshop Panels were constituted to address questions for presentation and discussion at the Conference held in Florence, Italy, May 7–9, 2015. At that time, a series of presentations were made, followed by in-depth discussions in an open forum. Each Workshop Panel also met in closed sessions to formulate the three evidence-based reports that accompany this summary statement. An Expert Panel then considered this information, developed summaries, guidelines, and a research agenda that constitutes this summary statement. Evidence: Preceding the conference, each Workshop Panel conducted an extensive literature search as noted in the individual manuscripts accompanying this report. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. Consensus Process: This report represents the Expert Panel's synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of hypoparathyroidism. Conclusions: This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of hypoparathyroidism.

AbstractAutomated methods are needed to facilitate high‐throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large‐scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37–0.87) and study (kappa range = 0.39–0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p‐value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000–4,500 cells: kappa = 0.78) than those with lower counts (50–500 cells: kappa = 0.41; p‐value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre‐ and post‐analytical quality control procedures are necessary in order to ensure satisfactory performance.

Objectives To identify distinct frailty trajectories (clusters of individuals following a similar progression of frailty over time) in an aging population and to estimate associations between frailty trajectories and emergency department visits, hospitalizations, and all‐cause mortality. Design Population‐based cohort study. Setting Olmsted County, Minnesota. Participants Olmsted County, Minnesota residents aged 60–89 in 2005. Measurements Longitudinal changes in frailty between 2005 and 2012 were measured by constructing a yearly Rockwood frailty index incorporating body mass index, 17 comorbidities, and 14 activities of daily living. The frailty index measures variation in health status as the proportion of deficits present of the 32 considered (range 0–1). Results Of the 16,443 Olmsted County residents aged 60–89 in 2005, 12,270 (74.6%) had at least 3 years of frailty index measures and were retained for analysis. The median baseline frailty index increased with age (0.11 for 60–69, 0.14 for 70–79, 0.19 for 80–89). Three distinct frailty trajectories were identified in individuals aged 60–69 at baseline and two trajectories in those aged 70–79 and 80–89. Within each decade of age, increasing frailty trajectories were associated with greater risks of emergency department visits, hospitalization, and all‐cause mortality, even after adjustment for baseline frailty index. Conclusion The number of frailty trajectories differed according to age. Within each age group, those in the highest frailty trajectory had greater healthcare use and worse survival. Frailty trajectories may offer a way to target aging individuals at high risk of hospitalization or death for therapeutic or preventive interventions.

Background— Contemporary data are lacking on the prognostic importance of heart failure (HF) after myocardial infarction (MI). We evaluated the prognostic impact of HF post MI according to preserved/reduced ejection fraction and the timing of its occurrence. Methods and Results— All Olmsted County, Minnesota, residents (n=2596) with incident MI diagnosed in 1990 to 2010 and no prior HF were followed through March 2013. Cox models were used to examine (1) the hazard ratios for death associated with HF type and timing and (2) secular trends in survival by HF status. During a mean follow-up of 7.6 years, there were 1116 deaths, 634 in the 902 patients who developed HF (70%) and 482 in the 1694 patients who did not develop HF (28%). After adjustment for age and sex, HF as a time-dependent variable was strongly associated with mortality (hazard ratio =3.31, 95% confidence interval: 2.93–3.75), particularly from cardiovascular causes (hazard ratio =4.20, 95% confidence interval: 3.50–5.03). Further adjustment for MI severity and comorbidity, acute treatment, and recurrent MI moderately attenuated these associations (hazard ratio =2.49 and 2.94 for all-cause and cardiovascular mortality, respectively). Mortality did not differ by ejection fraction, but was higher for delayed- versus early-onset HF ( P for heterogeneity =0.002). The age- and sex-adjusted 5-year survival estimates in 2001 to 2010 versus 1990 to 2000 were 82% and 81% among HF-free and 61% and 54% among HF patients, respectively ( P for heterogeneity of trends =0.05). Conclusions— HF markedly increases the risk of death after MI. This excess risk is similar regardless of ejection fraction but greater for delayed- versus early-onset HF. Mortality after MI declined over time, primarily as a result of improved HF survival.