Applied risk mapping and spatial analysis of address-level decedent data to inform opioid overdose interventions: The Massachusetts HEALing Communities Study.

BACKGROUND: Death certificate data provide powerful and sobering records of the opioid overdose crisis. In Massachusetts, where address-level decedent data are publicly available upon request, mapping and spatial analysis of fatal overdoses can provide valuable insights to inform prevention interventions. We describe how we used this approach to support a community-level intervention to reduce opioid-involved overdose mortality. METHODS: We developed a method to clean and geocode decedent data that substituted injury locations (the likely location of fatal overdoses) for deaths recorded in hospitals. After geomasking for greater privacy protection, we created maps to visualize the spatial distribution of decedent residence addresses, alone and juxtaposed with drive and walk-time distances to opioid treatment programs (OTPs), and place of death by overdose address. We used spatial statistical analyses to identify locations with significant clusters of overdoses. RESULTS: In the 8 intervention communities, 785 individuals died from opioid-involved overdoses between 2017 and 2020. We found that 19.7% of fatal overdoses were recorded in hospitals, 50.2% occurred at the decedent's residence, and 30.1% at another location. We identified overdose hotspots in study communities. By juxtaposing decedent residence data with drive- and walk-time analyses, we highlighted actionable spatial gaps in access to OTP treatment. CONCLUSION: To better understand local fatal opioid overdose risk environments and inform the development of community-level prevention interventions, we used publicly available address-level decedent data to conduct nuanced spatial analyses. Our approach can be replicated in other jurisdictions to inform overdose prevention responses.

Choosing Midwifery - The perceptions and experiences of Black, Asian and Minority Ethnic applicants to midwifery programmes: A mixed methods study.

AIM: to explore recruitment to UK midwifery programmes from the perspective of applicants from Black, Asian and Minority Ethnic (BAME) groups and describe the perceptions and experiences of the application process for these applicants and those from white backgrounds. BACKGROUND: Midwifery in the Global North is an overwhelmingly white profession. This lack of diversity has been cited as a factor in the poorer outcomes experienced by women from non-white backgrounds. There is a need for midwifery programmes to recruit and support more ethnically and racially diverse cohorts if this situation is to be addressed. Very little is currently known about the recruitment experiences of midwifery applicants. DESIGN: A mixed methods study comprising a survey and individual interview or focus group. The study was conducted between September 2020 and March 2021 in three universities in South East England. Participants comprised 440 applicants to midwifery programmes and 13 current or recently qualified BAME midwifery students. FINDINGS: Although many survey findings in respect to choosing a midwifery programme were broadly similar between candidates from BAME and non-BAME backgrounds, some trends were noted. More BAME applicants cited school/college rather than family as encouraging. More BAME applicants also indicated that they would consider issues of diversity when selecting a place of study, and BAME respondents appeared less likely to consider location and university life. Survey and focus group findings combined may indicate deficits in social capital available to BAME midwifery applicants. Focus group findings in particular suggest multiple experiences of challenge and inequity at all stages of the application process, together with a perception that midwifery is a niche and white profession. Applicants value proactive support from universities and would appreciate increased diversity, opportunities for mentorship and an individualised approach to recruitment. CONCLUSIONS: BAME applicants to midwifery can face additional challenges which have an impact on their ability to secure a place. There is a need to reposition midwifery as an inclusive and welcoming option for people from all backgrounds and to develop equitable recruitment processes that value a range of skills and life experiences.

Pharmacists' perceptions on real-time prescription monitoring (RTPM) systems - a cross-sectional survey.

Background: Real-time prescription monitoring (RTPM) systems are an effective tool to help health practitioners monitor opioid use and reduce opioid-related harm but little has been reported about the support required by pharmacists to engage with them effectively in practice. Objective: To evaluate the current understanding and perceptions of Western Australian pharmacists regarding RTPM systems and opioid-related harm, and investigate their self-reported training and support requirements prior to RTPM system implementation. Methods: This cross-sectional, prospective study involved an online Qualtrics survey distributed to Western Australian community or hospital pharmacists involved in dispensing and patient-centred roles via local professional pharmacy newsletters and social media. Data collection included demographic information, responses to authentic case scenarios and Likert-scale questions regarding perceptions and training requirements of a RTPM system, pain management and opioid-related harm. Descriptive analysis was utilised. Result: Sixty-two pharmacists responded to the questionnaire. Most (58/61; 95.1%) had a positive attitude towards RTPM systems, but only 33/61 (54.1%) reported being prepared for its implementation. Perceived barriers to successful implementation included lack of remuneration (46/60; 76.6%), conflict with prescribers (40/60; 66.7%), increased workload (37/60; 61.7%), staff safety concerns (34/60; 56.7%) and lack of knowledge regarding RTPM systems (32/60; 53.3%). Even though most participants were satisfied with training previously received, over 90% reported requiring further training and education, especially regarding RTPM systems (51/57; 96.2%) and opioid-related harm (56/57; 98.2%). Conclusion: Among a small sample of participants, there was a strong positivity regarding the value of RTPM systems and a high degree of receptiveness to further training in preparation for RTPM implementation.

Factors Associated With Normal Physiologic Birth for Women Who Labor In Water: A Secondary Analysis of A Prospective Observational Study.

INTRODUCTION: Research to understand factors associated with normal physiologic birth (unassisted vaginal birth, spontaneous labor onset without epidural analgesia, spinal, or general anesthetic, without episiotomy) is required. Laboring and/or giving birth in water has been shown to be associated with a high proportion of physiologic birth but with little understanding of factors that may influence this outcome. This study explored factors associated with normal physiologic birth for women who labored in water. METHODS: We conducted a secondary analysis of a UK-based prospective observational study of 8064 women at low risk of childbirth complications who labored in water. Consecutive women were recruited from birth settings in England, Scotland, and Northern Ireland. Planned place of birth, maternal characteristics, intrapartum events, and maternal and neonatal outcomes were measured. Univariable and multivariable logistic regression modelling explored factors associated with normal physiologic birth. RESULTS: In total, 5758 (71.4%) of women who labored in water had a normal physiologic birth. Planned birth in the community (adjusted odds ratio [aOR], 2.58; 95% CI, 2.22-2.99) or at an alongside midwifery unit (aOR, 1.21; 95% CI, 1.04-1.41) was positively associated with normal physiologic birth compared with planned birth in an obstetric unit. Duration of second stage (aOR, 0.66; 95% CI, 0.62-0.70), duration in the pool [aOR, 0.93; 95% CI, 0.90-0.96), and birth weight of the neonate (aOR, 0.74; 95% CI, 0.65-0.85) were negatively associated with normal physiologic birth. Parity was not associated with normal physiologic birth in multivariate analyses. DISCUSSION: Our findings largely reflected wider research, both in and out of water. We found midwifery-led birth settings may increase the likelihood of normal physiologic birth among healthy women who labor in water, irrespective of parity. This association supports growing evidence demonstrating the importance of planned place of birth on reducing intervention rates and adds to research on labor and birth in water.

Stewardship Intervention to Optimize Central Venous Catheter Utilization in Critically Ill Children.

We aimed to describe utilization and indication(s) for long-term central venous catheters (CVCs) in a pediatric intensive care unit (PICU) and identify potential strategies to decrease CVC utilization. METHODS: We conducted a single-center prospective quality improvement initiative at a 30-bed PICU in a large, freestanding, academic children's hospital. We created an electronic report to identify patients with an indwelling CVC for 7 days and older (defined as long term). We discussed the ongoing need for each long-term CVC with PICU clinicians at weekly interdisciplinary structured "CVC stewardship rounds." We then made recommendations around expedited removal of CVCs. We conducted multiple Plan-Do-Study-Act cycles to categorize CVC indications, identify modifiable factors, and educate PICU clinicians. We hypothesized that CVC stewardship rounds would decrease long-term CVC utilization in our PICU. RESULTS: From October 2016 to September 2017, 607 long-term CVCs were eligible for the stewardship intervention. Compared to the preintervention period, we recorded a significant increase in peripherally inserted central catheters and a decrease in nontunneled CVCs (P < 0.001). Most patients had single- or double-lumen CVCs in both the preintervention and intervention periods (86% and 91%, respectively). The utilization of overall long-term CVC devices, and those with modifiable indications, decreased during the intervention period. CONCLUSIONS: A single-center QI intervention focused on PICU CVC stewardship was associated with a decrease in CVC utilization.

Building Research Support Capacity across Human Health Biobanks during the COVID-19 Pandemic.

Human health biobanks are forms of research infrastructure that supply biospecimens and associated data to researchers, and therefore juxtapose the activities of clinical care and biomedical research. The discipline of biobanking has existed for over 20 years and is supported by several international professional societies and dedicated academic journals. However, despite both rising research demand for human biospecimens, and the growth of biobanking as an academic discipline, many individual biobanks continue to experience sustainability challenges. This commentary will summarize how the COVID-19 pandemic is creating new challenges and opportunities for both the health biobanking sector and the supporting discipline of biobanking. While the challenges for biobanks may be numerous and acute, there are opportunities for both individual biobanks and the discipline of biobanking to embrace change such that biobanks can continue to support and drive biomedical research. We will therefore describe numerous practical steps that individual biobanks and/or the discipline of biobanking can take to survive and possibly thrive in response to the COVID-19 pandemic.

Trends in Pediatric Candidemia: Epidemiology, Anti-Fungal Susceptibility, and Patient Characteristics in a Children's Hospital.

Candida bloodstream infections (CBSIs) have decreased among pediatric populations in the United States, but remain an important cause of morbidity and mortality. Species distributions and susceptibility patterns of CBSI isolates diverge widely between children and adults. The awareness of these patterns can inform clinical decision-making for empiric or pre-emptive therapy of children at risk for candidemia. CBSIs occurring from 2006-2016 among patients in a large children's hospital were analyzed for age specific trends in incidence rate, risk factors for breakthrough-CBSI, and death, as well as underlying conditions. Candida species distributions and susceptibility patterns were evaluated in addition to the anti-fungal agent use. The overall incidence rate of CBSI among this complex patient population was 1.97/1000 patient-days. About half of CBSI episodes occurred in immunocompetent children and 14% in neonatal intensive care unit (NICU) patients. Anti-fungal resistance was minimal: 96.7% of isolates were fluconazole, 99% were micafungin, and all were amphotericin susceptible. Liposomal amphotericin was the most commonly prescribed anti-fungal agent included for NICU patients. Overall, CBSI-associated mortality was 13.7%; there were no deaths associated with CBSI among NICU patients after 2011. Pediatric CBSI characteristics differ substantially from those in adults. The improved management of underlying diseases and antimicrobial stewardship may further decrease morbidity and mortality from CBSI, while continuing to maintain low resistance rates among Candida isolates.

Practice Improvement for Standardized Evaluation and Management of Acute Tracheitis in Mechanically Ventilated Children.

There is no consensus definition for ventilator-associated tracheitis and limited evidence to guide diagnosis and treatment. To improve acute tracheitis evaluation and management, this quality improvement project aimed to (1) improve the appropriateness of tracheal aspirate cultures while decreasing the number of unnecessary cultures by 20% and (2) decrease antibiotic use for acute tracheitis not consistent with local guidelines by 20% over 12 months among pediatric patients requiring mechanical ventilation. METHODS: All patients admitted to the Medical Intensive Care Unit requiring mechanical ventilation via an artificial airway were included. Tracheal aspirate sampling criteria, technique, and minimum intervals were standardized. Primary outcome measures were the number of tracheal aspirate cultures obtained per 100 ETT/tracheostomy days and ventilator-associated antibiotic days per 100 ETT/tracheostomy days. Improvement cycles included: Implementation of tracheal aspirate sampling criteria, sampling technique standardization, limiting repeat cultures to >72-hour intervals, and standardizing empiric antibiotic therapy. RESULTS: Tracheal aspirate culture rate decreased from 10.70 to 7.10 cultures per 100 ETT/tracheostomy days (P < 0.001). Cultures meeting sampling criteria increased from 28% to 80%. Ventilator-associated antibiotic use decreased from 24.88 to 7.30 ventilator-associated antibiotic days per 100 ETT/tracheostomy days. There were no associated increases in ventilator-associated events or days of mechanical ventilation. CONCLUSIONS: Implementation of standardized criteria for tracheal aspirate sampling, improved tracheal aspirate sampling technique, limiting repeat tracheal aspirate cultures, and utilizing standardized antibiotic treatment guidelines safely decreased resource utilization and antibiotic use among critically ill children requiring mechanical ventilation.

Central venous catheter bundle adherence: Kamishibai card (K-card) rounding for central-line-associated bloodstream infection (CLABSI) prevention.

OBJECTIVE: To institute facility-wide Kamishibai card (K-card) rounding for central venous catheter (CVC) maintenance bundle education and adherence and to evaluate its impact on bundle reliability and central-line-associated bloodstream infection (CLABSI) rates. DESIGN: Quality improvement project. SETTING: Inpatient units at a large, academic freestanding children's hospital. PARTICIPANTS: Data for inpatients with a CVC in place for ≥1 day between November 1, 2017 and October 31, 2018 were included. INTERVENTION: A K-card was developed based on 7 core elements in our CVC maintenance bundle. During monthly audits, auditors used the K-cards to ask bedside nurses standardized questions and to conduct medical record documentation reviews in real time. Adherence to every bundle element was required for the audit to be considered "adherent." We recorded bundle reliability prospectively, and we compared reliability and CLABSI rates at baseline and 1 year after the intervention. RESULTS: During the study period, 2,321 K-card audits were performed for 1,051 unique patients. Overall maintenance bundle reliability increased significantly from 43% at baseline to 78% at 12 months after implementation (P < .001). The hospital-wide CLABSI rate decreased from 1.35 during the 12-month baseline period to 1.17 during the 12-month intervention period, but the change was not statistically significant (incidence rate ratio [IRR], 0.87; 95% confidence interval [CI], 0.60-1.24; P = .41). CONCLUSIONS: Hospital-wide CVC K-card rounding facilitated standardized data collection, discussion of reliability, and real-time feedback to nurses. Maintenance bundle reliability increased after implementation, accompanied by a nonsignificant decrease in the CLABSI rate.

Predictors of obstetric anal sphincter injury during waterbirth: a secondary analysis of a prospective observational study.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injury (OASI) during childbirth is associated with urino-genital pain and dysfunction. Waterbirth is a popular birth choice for women, but controversy remains around the risk of OASI during waterbirth. This study reports on the incidence of OASI, and factors associated with OASI, for a cohort of women who gave birth in water. METHODS: This secondary analysis used prospectively collected data from 2,908 women who gave birth in water in a hospital setting. The incidence of OASI was calculated. Univariable and multivariable logistic regression analysis evaluated factors associated with OASI. RESULTS: The incidence of OASI was 1.9% (95% confidence interval (CI) 1.4, 2.4) for all women. In nulliparae it was higher (3.2%, 95% CI 2.3, 4.3) than in multiparae (0.9%, 95% CI 0.5, 1.4). In the multivariable analysis, two variables were associated with OASI; multiparity was negatively associated with OASI (adjusted odds ratio [aOR] 0.24, 95% CI 0.12, 0.50, p < 0.001), and birth weight was positively associated with OASI (aOR 1.001, 95% CI 1.000, 1.002, p = 0.02). A "hands-on" technique was used during only 13% of births. A birth position supporting a flexible sacrum did not influence OASI risk. CONCLUSIONS: A low incidence of OASI was found for this cohort of women. The low proportion of midwives using a hands-on technique suggests that it may not be required in waterbirth.

Toward a Synergistic Operating Model for Westmead Research Hub Biobanks: A Questionnaire Study.

Standardization and sustainability are ideals within the biobanking world, and the demand for high-quality well-annotated specimens is growing just as rapidly as the ever-increasing precision and throughput of today's high-tech scientific methods. In the state of New South Wales (NSW) in Australia, the state government has allocated significant funding toward this requirement in recent years, with the launch of the NSW Health Statewide Biobank in central Sydney in 2017, and the introduction of the voluntary NSW Biobank Certification Program, and Consent Toolkit. For new and established biobanks, the influence of these new resources has been twofold: first they have provided valuable guidance for moving toward standardized practices and raising the bar for biobanking quality standards; second, they have brought to the forefront the challenges of sustainability and transitioning to a certification standard of biobanking. In Westmead, ∼20 km from Sydney's central business district, the Westmead Research Hub has responded to these challenges with a collaborative biobanking project initiated in 2015. As the site of almost 30 individual biobanks, and to inform a pilot project of central biobank services, a questionnaire was developed and administered to all of the biobanks. This article reports on the results from the questionnaire and the rationale for subsequent initiation of a core biobanking facility.

Enhanced central venous catheter bundle for pediatric parenteral-dependent intestinal failure.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) cause substantial morbidity and increase antimicrobial use and length of stay among hospitalized children in the United States. CLABSI occurs more frequently among high-risk pediatric patients, such as those with intestinal failure (IF) who are parenteral nutrition (PN) dependent. Following an increase in CLABSI rates, a quality improvement (QI) initiative was implemented. METHODS: Using QI methodology, an enhanced central venous catheter (CVC) maintenance bundle was developed and implemented on 2 units for pediatric PN-dependent patients with IF. CLABSI rates were prospectively monitored pre- and postimplementation, and bundle element adherence was monitored. Enhanced bundle elements included chlorhexidine-impregnated patch, daily bathing, ethanol locks, 2 nurses for CVC care in a distraction-free zone, peripheral laboratory draws, bundling routine laboratory tests, and PN administration set changes every 24 hours. RESULTS: Adherence to enhanced bundle elements increased to >90% over 3 months. CLABSI rates averaged 1.41 per 1,000 central line days preimplementation compared with 0.40 per 1,000 device days postimplementation (P = .003), an 85% absolute reduction in CLABSI rates over 12 months. CONCLUSIONS: Patients with IF are at an increased risk for CLABSI. Enhanced CVC maintenance bundles that specifically target prevention practices in this population may be beneficial.

An Australian Biobank Certification Scheme: A Study of Economic Costs to Participating Biobanks.

Biobanks face increasing demands for research materials of consistent quality, which can be used in collaborative studies. Several countries and some international agencies have made formal efforts to standardize biobank operations and outputs. These include the establishment of best practice guidelines for collection management, and certification programs. Such guidelines and programs increase biobanks' opportunities for participation in high impact research and funding. However, they also impose economic and time costs, which may burden biobanks. This study aimed to estimate the costs of gaining certification and maintaining certification (i.e., committing extra resources to continue standards) for three cancer biobanks participating in a biobank certification program in New South Wales, Australia. To gather cost data for a range of cancer biobanks, we recruited three with different full time equivalent (FTE) staff levels (1.0-3.0), recognizing FTE staff level as an indicator of resources and operating scale. In extended interviews with staff, we gathered biobanks' expected costs in obtaining and annually maintaining certification. The biobank with the highest staff level reported the lowest expected costs in gaining certification, due to the strong prealignment of its present operations with certification requirements. The other biobanks expected higher costs as their operations required greater adjustments. Overall, relative costs of gaining certification were between 2% and 6% of current total annual wage costs. To the authors' knowledge, this is the first such costing study of a biobank certification program. Supplementary Data include the interview schedule that other biobanks may use to estimate their own economic certification costs.

Reducing Redundant Anaerobic Therapy Through Spaced Education and Antimicrobial Stewardship Interventions.

BACKGROUND: Decreasing the use of redundant anaerobic therapy is a key target for antimicrobial stewardship. Education techniques that optimize knowledge retention could be an important component of reducing these regimens. METHODS: We implemented a quality improvement project that incorporated spaced education to reduce the use of redundant anaerobic therapy. The initial interventions (November through December 2015) included education in a hospital-wide newsletter and review of redundant anaerobic regimens by the antimicrobial stewardship program. A spaced education module was then developed with the gastroenterology (GI) service, which had a relatively high rate of redundant anaerobic therapy use. Ten questions with teaching points were delivered to GI physicians at spaced intervals over 2 to 4 weeks (February through March 2016). Knowledge scores were compared at initial and final question presentation using generalized estimating equations. Interrupted time-series analysis was used to compare the rates of redundant-metronidazole-days per 1000 patient-days among patients in the patients admitted to the GI service and those in the non-GI group before and after the intervention. RESULTS: Of 66 GI physicians, 56 (85%) participated in the spaced education activity. After the intervention, their knowledge scores on all the questions improved, and their mean knowledge score increased from 57% to 86% (P < .001). Nearly all (91%) of the participants were very or generally satisfied with the activity. In the GI group, the rate of redundant-metronidazole-days decreased from 26.2 to 13.0 per 1000 patient-days (relative risk [RR], 0.45 [95% confidence interval (CI), 0.27-0.73]; P = .001). This rate in the non-GI group also decreased from 5.47 to 2.18 per 1000 patient-days (RR, 0.47 [95% CI, 0.36-0.60]; P < .001) after our interventions. CONCLUSIONS: Spaced education is an effective approach for teaching antimicrobial stewardship topics. Focused provider education was associated with a sustained reduction in the use of redundant anaerobic therapy.

Is Your Biobank Up to Standards? A Review of the National Canadian Tissue Repository Network Required Operational Practice Standards and the Controlled Documents of a Certified Biobank.

Ongoing quality management is an essential part of biobank operations and the creation of high quality biospecimen resources. Adhering to the standards of a national biobanking network is a way to reduce variability between individual biobank processes, resulting in cross biobank compatibility and more consistent support for health researchers. The Canadian Tissue Repository Network (CTRNet) implemented a set of required operational practices (ROPs) in 2011 and these serve as the standards and basis for the CTRNet biobank certification program. A review of these 13 ROPs covering 314 directives was conducted after 5 years to identify areas for revision and update, leading to changes to 7/314 directives (2.3%). A review of all internal controlled documents (including policies, standard operating procedures and guides, and forms for actions and processes) used by the BC Cancer Agency's Tumor Tissue Repository (BCCA-TTR) to conform to these ROPs was then conducted. Changes were made to 20/106 (19%) of BCCA-TTR documents. We conclude that a substantial fraction of internal controlled documents require updates at regular intervals to accommodate changes in best practices. Reviewing documentation is an essential aspect of keeping up to date with best practices and ensuring the quality of biospecimens and data managed by biobanks.

Evaluation of Control Strategies for Porcine Reproductive and Respiratory Syndrome (PRRS) in Swine Breeding Herds Using a Discrete Event Agent-Based Model.

The objective of this study was to develop a discrete event agent-based stochastic model to explore the likelihood of the occurrence of porcine reproductive and respiratory syndrome (PRRS) outbreaks in swine herds with different PRRS control measures in place. The control measures evaluated included vaccination with a modified-live attenuated vaccine and live-virus inoculation of gilts, and both were compared to a baseline scenario where no control measures were in place. A typical North American 1,000-sow farrow-to-wean swine herd was used as a model, with production and disease parameters estimated from the literature and expert opinion. The model constructed herein was not only able to capture individual animal heterogeneity in immunity to and shedding of the PRRS virus, but also the dynamic animal flow and contact structure typical in such herds under field conditions. The model outcomes included maximum number of females infected per simulation, and time at which that happened and the incidence of infected weaned piglets during the first year of challenge-virus introduction. Results showed that the baseline scenario produced a larger percentage of simulations resulting in outbreaks compared to the control scenarios, and interestingly some of the outbreaks occurred over long periods after virus introduction. The live-virus inoculation scenario showed promising results, with fewer simulations resulting in outbreaks than the other scenarios, but the negative impacts of maintaining a PRRS-positive population should be considered. Finally, under the assumptions of the current model, neither of the control strategies prevented the infection from spreading to the piglet population, which highlights the importance of maintaining internal biosecurity practices at the farrowing room level.

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.