Nicole F. Dowling

The continuum of translation research in genomic medicine: how can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention?

Advances in genomics have led to mounting expectations in regard to their impact on health care and disease prevention. In light of this fact, a comprehensive research agenda is needed to move human genome discoveries into health practice in a way that maximizes health benefits and minimizes harm to individuals and populations. We present a framework for the continuum of multidisciplinary translation research that builds on previous characterization efforts in genomics and other areas in health care and prevention. The continuum includes four phases of translation research that revolve around the development of evidence-based guidelines. Phase 1 translation (T1) research seeks to move a basic genome-based discovery into a candidate health application (e.g., genetic test/intervention). Phase 2 translation (T2) research assesses the value of a genomic application for health practice leading to the development of evidence-based guidelines. Phase 3 translation (T3) research attempts to move evidence-based guidelines into health practice, through delivery, dissemination, and diffusion research. Phase 4 translation (T4) research seeks to evaluate the “real world” health outcomes of a genomic application in practice. Because the development of evidence-based guidelines is a moving target, the types of translation research can overlap and provide feedback loops to allow integration of new knowledge. Although it is difficult to quantify how much of genomics research is T1, we estimate that no more than 3% of published research focuses on T2 and beyond. Indeed, evidence-based guidelines and T3 and T4 research currently are rare. With continued advances in genomic applications, however, the full continuum of translation research needs adequate support to realize the promise of genomics for human health.

Sodium and Potassium Intake and Mortality Among US Adults: Prospective Data From the Third National Health and Nutrition Examination Survey

BACKGROUND Several epidemiologic studies suggested that higher sodium and lower potassium intakes were associated with increased risk of cardiovascular diseases (CVD). Few studies have examined joint effects of dietary sodium and potassium intake on risk of mortality. METHODS To investigate estimated usual intakes of sodium and potassium as well as their ratio in relation to risk of all-cause and CVD mortality, the Third National Health and Nutrition Examination Survey Linked Mortality File (1988-2006), a prospective cohort study of a nationally representative sample of 12,267 US adults, studied all-cause, cardiovascular, and ischemic heart (IHD) diseases mortality. RESULTS During a mean follow-up period of 14.8 years, we documented a total of 2270 deaths, including 825 CVD deaths and 443 IHD deaths. After multivariable adjustment, higher sodium intake was associated with increased all-cause mortality (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.03-1.41 per 1000 mg/d), whereas higher potassium intake was associated with lower mortality risk (HR, 0.80; 95% CI, 0.67-0.94 per 1000 mg/d). For sodium-potassium ratio, the adjusted HRs comparing the highest quartile with the lowest quartile were HR, 1.46 (95% CI, 1.27-1.67) for all-cause mortality; HR, 1.46 (95% CI, 1.11-1.92) for CVD mortality; and HR, 2.15 (95% CI, 1.48-3.12) for IHD mortality. These findings did not differ significantly by sex, race/ethnicity, body mass index, hypertension status, education levels, or physical activity. CONCLUSION Our findings suggest that a higher sodium-potassium ratio is associated with significantly increased risk of CVD and all-cause mortality, and higher sodium intake is associated with increased total mortality in the general US population.

Age and the prevalence of bleeding disorders in women with menorrhagia.

OBJECTIVE: A study was conducted to evaluate the frequency and types of hemostatic defects occurring in adolescent and perimenopausal-age women diagnosed with menorrhagia. METHODS: A total of 115 women with a physician diagnosis of menorrhagia, including 25 adolescent women, 25 perimenopausal-age women, and 65 women between the ages of 20 and 44, underwent comprehensive hemostatic testing for possible bleeding disorders. Frequencies of bleeding disorders were calculated and compared. RESULTS: Forty-seven percent of women were found to have hemostatic abnormalities, including platelet dysfunction, von Willebrand’s disease, and coagulation factor deficiencies. Adolescents and perimenopausal-age women with menorrhagia were just as likely to have hemostatic abnormalities as were women aged 20 to 44. CONCLUSION: These results demonstrate that underlying bleeding disorders are frequently found in adolescent, postadolescent reproductive age, and perimenopausal-age women presenting with menorrhagia and suggest that women with menorrhagia should be considered for further hemostatic evaluation. LEVEL OF EVIDENCE: II-2

Periprocedural anticoagulation management of patients with nonvalvular atrial fibrillation.

OBJECTIVE To estimate the 3-month cumulative incidence of thromboembolism (TE), bleeding, and death among consecutive patients with nonvalvular atrial fibrillation (AF) who were receiving long-term anticoagulation therapy and were referred to the Thrombophilia Center at Mayo Clinic for periprocedural anticoagulation management. PATIENTS AND METHODS In a prospective cohort study of consecutive patients receiving long-term anticoagulation therapy who were referred to the Thrombophilia Center for periprocedural anticoagulation management over the 7-year period, January 1, 1997, to December 31, 2003, 345 patients with nonvalvular AF were eligible for inclusion. Warfarin was stopped 4 to 5 days before and was restarted after surgery as soon as hemostasis was assured. The decision to provide bridging therapy with heparin was individualized and based on the estimated risks of TE and bleeding. RESULTS The 345 patients with AF (mean +/- SD age, 74+/-9 years; 33% women) underwent 386 procedures. Warfarin administration was not interrupted for 44 procedures. Periprocedural heparin was provided for 204 procedures. Patients receiving heparin were more likely to have prior TE (43% vs 24%; P<.001) and a higher CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke) score (2.2 vs 1.9; P=.06). Four patients had 6 episodes of TE (3 strokes and 3 acute coronary episodes; TE rate, 1.1%; 95% confidence interval, 0.0%-2.1%). Nine patients had 10 major bleeding events (major bleeding rate, 2.7%; 95% confidence interval, 1.0%-4.4%). There were no deaths. Neither bleeding nor TE rates differed by anticoagulant management strategy. CONCLUSION The 3-month cumulative incidence of TE and bleeding among patients with AF in whom anticoagulation was temporarily interrupted for an invasive procedure was low and was not significantly influenced by bridging therapy.

Population red blood cell folate concentrations for prevention of neural tube defects: bayesian model

Objective To determine an optimal population red blood cell (RBC) folate concentration for the prevention of neural tube birth defects. Design Bayesian model. Setting Data from two population based studies in China. Participants 247 831 participants in a prospective community intervention project in China (1993-95) to prevent neural tube defects with 400 μg/day folic acid supplementation and 1194 participants in a population based randomized trial (2003-05) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age. Intervention Folic acid supplementation (400 μg/day). Main outcome measures Estimated RBC folate concentration at time of neural tube closure (day 28 of gestation) and risk of neural tube defects. Results Risk of neural tube defects was high at the lowest estimated RBC folate concentrations (for example, 25.4 (95% uncertainty interval 20.8 to 31.2) neural tube defects per 10 000 births at 500 nmol/L) and decreased as estimated RBC folate concentration increased. Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L (for example, 6 neural tube defects per 10 000 births at 1180 (1050 to 1340) nmol/L). The modeled dose-response relation was consistent with the existing literature. In addition, neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid. Conclusions A threshold for “optimal” population RBC folate concentration for the prevention of neural tube defects could be defined (for example, approximately 1000 nmol/L). Population based RBC folate concentrations, as a biomarker for risk of neural tube defects, can be used to facilitate evaluation of prevention programs as well as to identify subpopulations at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency.

Multisite management study of menorrhagia with abnormal laboratory haemostasis: A prospective crossover study of intranasal desmopressin and oral tranexamic acid

The optimal management of menorrhagia among women with abnormal laboratory haemostasis is uncertain. In a crossover study, 116 women with menorrhagia [pictorial blood assessment chart (PBAC) score >100], negative gynaecological evaluation and abnormal laboratory haemostasis were randomly assigned to either intranasal desmopressin (IN‐DDAVP) or tranexamic acid (TA) therapy for two menstrual cycles. The subjects then crossed over to the second study drug for two additional cycles. Menstrual blood loss (MBL) was measured by PBAC scores at baseline and after each menstrual cycle. Quality of life (QOL) was assessed with four validated instruments. There was a statistically significant decrease in PBAC scores for both treatments. On average, the estimated decrease in the PBAC from baseline was −64·1 [95% confidence interval (CI) = −88·0, −40·3] for IN‐DDAVP and −105·7 (95% CI = −130·5, −81·0) for TA. The decrease in PBAC score was greater for TA than IN‐DDAVP (a difference of 41·6, P‐value = 0·0002, 95% CI = 19·6, 63·6). The test for treatment‐type effect was significant (P < 0·0001) suggesting a greater reduction in PBAC score with TA. Use of both IN‐DDAVP and TA improved QOL by all four instruments. We conclude that both medications reduced MBL and improved QOL among females with menorrhagia and abnormal laboratory haemostasis, but TA proved more effective.

Prevalence in the United States of Selected Candidate Gene Variants Third National Health and Nutrition Examination Survey, 1991–1994

Population-based allele frequencies and genotype prevalence are important for measuring the contribution of genetic variation to human disease susceptibility, progression, and outcomes. Population-based prevalence estimates also provide the basis for epidemiologic studies of gene–disease associations, for estimating population attributable risk, and for informing health policy and clinical and public health practice. However, such prevalence estimates for genotypes important to public health remain undetermined for the major racial and ethnic groups in the US population. DNA was collected from 7,159 participants aged 12 years or older in Phase 2 (1991–1994) of the Third National Health and Nutrition Examination Survey (NHANES III). Certain age and minority groups were oversampled in this weighted, population-based US survey. Estimates of allele frequency and genotype prevalence for 90 variants in 50 genes chosen for their potential public health significance were calculated by age, sex, and race/ethnicity among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. These nationally representative data on allele frequency and genotype prevalence provide a valuable resource for future epidemiologic studies in public health in the United States.

Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis

BACKGROUND Childhood asthma has become a critical public health problem because of its high morbidity and increasing prevalence. The impact of nutrition and other exposures during pregnancy on long-term health and development of children has been of increasing interest. OBJECTIVE We performed a systematic review and meta-analysis of the association of folate and folic acid intake during pregnancy and risk of asthma and other allergic outcomes in children. DESIGN We performed a systematic search of 8 electronic databases for articles that examined the association between prenatal folate or folic acid exposure and risk of asthma and other allergic outcomes (eg, allergy, eczema, and atopic dermatitis) in childhood. We performed a meta-analysis by using a random-effects model to derive a summary risk estimate of studies with similar exposure timing, exposure assessment, and outcomes. RESULTS Our meta-analysis provided no evidence of an association between maternal folic acid supplement use (compared with no use) in the prepregnancy period through the first trimester and asthma in childhood (summary risk estimate: 1.01; 95% CI: 0.78, 1.30). Because of substantial heterogeneity in exposures and outcomes, it was not possible to generate summary measures for other folate indicators (eg, blood folate concentrations) and asthma or allergy-related outcomes; however, the preponderance of primary risk estimates was not elevated. CONCLUSIONS Our findings do not support an association between periconceptional folic acid supplementation and increased risk of asthma in children. However, because of the limited number and types of studies in the literature, additional research is needed.

Periprocedural Anticoagulation Management of Patients With Venous Thromboembolism

Objective—Patients with venous thromboembolism (VTE) often require temporary warfarin interruption for an invasive procedure. The incidence of thromboembolism and bleeding related to periprocedural anticoagulation management of such patients is unknown. Methods and Results—In a protocol-driven, inception cohort design study, all VTE patients (n=775) referred for periprocedural anticoagulation management (1997–2007) were followed-up to estimate the 3-month cumulative incidence of thromboembolism and bleeding. Patients were stratified by thrombus acuity (acute, <30 days; subacute, 31–90 days; or chronic ≥91 days). Decisions to provide “bridging” low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Low-molecular-weight heparin was more often administered in acute (87%) and subacute (81%) VTE compared to chronic VTE (59%; P<0.001). The 3-month cumulative incidence of thromboembolism (1.8%), major hemorrhage (1.8%), and mortality (1.7%) were low and did not differ by management strategy. Active cancer was the only independent predictor of thrombotic recurrence (HR, 4.86; 95% CI, 1.6–14.5; P=0.005), major hemorrhage (HR, 6.8; 95% CI, 2.1–21.7; P=0.001), and death (HR, 32.7; 95% CI, 4.3–251.2; P=0.0008). Conclusion—Thromboembolism, bleeding, and death among VTE patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Cancer patients require particular care given their propensity for both clotting and bleeding.

Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation

OBJECTIVE A study was conducted to develop a short, easy to administer screening tool useful for stratifying women with unexplained menorrhagia for hemostatic testing for underlying bleeding disorders. STUDY DESIGN One hundred forty-six women with a physician diagnosis of menorrhagia underwent comprehensive hemostatic testing for the diagnosis of bleeding disorders, including von Willebrand disease, platelet dysfunction, and coagulation factor deficiencies. A 12 page questionnaire of bleeding symptoms was administered. Bleeding symptoms with high predictive values for laboratory hemostatic abnormalities were combined and used as single variables to calculate sensitivity, specificity, and positive and negative predictive values in order to develop a short screening tool to identify females for testing and evaluation. RESULTS A combination of 8 questions in 4 categories resulted in a sensitivity of 82% (95%CI 75-90) for bleeding disorders. Adding a pictorial blood assessment chart score > 100 increased the sensitivity of the screening tool to 95% (95%CI 91-99). CONCLUSION These results demonstrate the feasibility of a simple questionnaire based screening tool to identify females for testing and evaluation for bleeding disorders.