Ethics Committees: Team Perspectives and Organizational Responses.

Healthcare ethics committees can be valuable resources but are largely underutilized by nurses. The purpose of this project was to review ethics concerns and educational needs of nurses in a large, integrated healthcare delivery system. Seven themes were identified: organizational issues, nonbeneficial care, withdrawing life-sustaining therapies, discharge disposition, challenging patients and families, communication with physicians, and capacity versus competence. A process was then developed to better engage nurses in ethical discussions.

A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers.

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.

How Do Patients Respond to Genetic Testing for Age-related Macular Degeneration?

SIGNIFICANCE: The American Academy of Ophthalmology currently recommends against routine genetic testing for complex diseases such as age-related macular degeneration (AMD). The results of this study demonstrate that patients are very interested in predictive genetic testing for AMD, find the information useful, and make behavioral changes as a result of the information. PURPOSE: The goal of this project was to conduct a pilot AMD genomic medicine study. METHODS: Eligible patients were aged 50 to 65 years with no personal history of AMD. DNA samples were genotyped for five single-nucleotide polymorphisms (SNPs) in the CFH gene, one SNP in the ARMS-2 gene, one SNP in the C3 gene, and one SNP in the mitochondrial ND2 gene. A risk score was calculated utilizing a model based on odds ratios, lifetime risk of advanced AMD and known population prevalence of genotype, haplotype, and smoking risk. The study optometrist provided the patient's risk score and counseling for personal protective behaviors. Telephone interviews were conducted 1 to 3 months after the counseling visit. RESULTS: One hundred one subjects (85%) participated in the genetic testing; 78 (77.2%) were female. Follow-up interviews were conducted with 94 participants (93.1%). More than half (n = 48) of the participants said that they were motivated to participate in the study because they had a family member with AMD or another eye or genetic disorder. Despite low risk levels, many participants reported making changes as a result of the genetic testing. Twenty-seven people reported making specific changes, including wearing sunglasses and brimmed hat and taking vitamin supplements. Another 16 people said that they were already doing the recommended activities, including wearing glasses, quitting smoking, and/or taking vitamins. CONCLUSIONS: Interest in genetic testing for future risk of AMD was high in this population and resulted in support to continue current health behaviors or incentive to improve behaviors related to eye health.

Strategies for integrating personalized medicine into healthcare practice.

AIM: Research and innovation in personalized medicine are surging, however, its adoption into clinical practice is comparatively slow. We identify common challenges to the clinical adoption of personalized medicine and provide strategies for addressing these challenges. METHODS: Our team developed a list of common challenges through a series of group discussions, surveys and interviews, and convened a national summit to discuss solutions for overcoming these challenges. We used a framework approach for thematic analysis. RESULTS: We categorized challenges into five areas of need: education and awareness; patient empowerment; value recognition; infrastructure and information management; and ensuring access to care. We then developed strategies to address these challenges. CONCLUSION: In order for healthcare to transition into personalized medicine, it is necessary for stakeholders to build momentum by implementing a progression of strategies.

The use of dietary supplements and their association with blood pressure in a large Midwestern cohort.

BACKGROUND: There have been numerous studies assessing the association of diet and blood pressure but little is known about the association between less commonly used nutritional supplements and blood pressured. The purpose of this study was to quantify the use of dietary supplements and their potential association with blood pressure in a large population-based cohort of adults in the Midwest. METHODS: The Personalized Medicine Research Project cohort was the population source for the current study. The current study includes subjects with Dietary History Questionnaire (DHQ) data available as well as at least one clinical blood pressure measurement recorded in their electronic medical record. After excluding extreme outlying measurements, median systolic and diastolic blood pressure measurements were calculated for each individual and were compared for subjects who did and did not report taking one of a list of 37 different supplements listed on the DHQ more than once per week over the previous 12 months. RESULTS: 9,732 subjects had both blood pressure and DHQ data available. They ranged in age from 18 to 98 years (mean 56 years) and 3,625 (37%) were male. Nine of 37 supplements showed evidence for association with blood pressure: coenzyme Q10, fish oil, iron, bilberry, echinacea, evening primrose oil, garlic, goldenseal and milk thistle. With the exception of the mineral iron, mean systolic and diastolic blood pressures were higher for users of the specific supplements than non-users. CONCLUSIONS: These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. We hope the observed significant associations will foster future research to evaluate blood pressure effects of dietary supplements.

Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer.

PURPOSE: The aim of this study was to examine Lynch syndrome screening of patients with metastatic colorectal cancer in integrated health-care-delivery organizations. METHODS: We determined the availability of Lynch syndrome screening criteria and actual Lynch syndrome screening in the medical records of 1,188 patients diagnosed with metastatic colorectal cancer between 2004 and 2009 at seven institutions in the Cancer Research Network. RESULTS: We found infrequent use of Lynch syndrome screening (41/1,188). Family history was available for 937 of the 1,188 patients (79%). There was sufficient information to assess Lynch syndrome risk using family history-based criteria in 719 of the 937 patients (77%) with family history documentation. In 391 individuals with a family history of a Lynch syndrome-associated cancer, 107 (27%) could not be evaluated due to missing information such as age of cancer onset. Eleven percent of patients who met the Bethesda criteria and 25% of individuals who met the Amsterdam II criteria were screened for Lynch syndrome. Recommended guidelines were adhered to during screening, but no testing method was preferred. CONCLUSION: The information required for Lynch syndrome screening decisions is routinely collected but seldom used. There is a critical gap between collection of family history and its use to guide Lynch syndrome screening, which may support a case for implementation of universal screening guidelines.

Pollen count and presentation of angiotensin-converting enzyme inhibitor-associated angioedema.

BACKGROUND: The incidence of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema is increased in patients with seasonal allergies. OBJECTIVE: We tested the hypothesis that patients with ACE inhibitor-associated angioedema present during months when pollen counts are increased. METHODS: Cohort analysis examined the month of presentation of ACE inhibitor-associated angioedema and pollen counts in the ambulatory and hospital setting. Patients with ACE inhibitor-associated angioedema were ascertained through (1) an observational study of patients presenting to Vanderbilt University Medical Center, (2) patients presenting to the Marshfield Clinic and participating in the Marshfield Clinic Personalized Medicine Research Project, and (3) patients enrolled in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Measurements include date of presentation of ACE inhibitor-associated angioedema, population exposure to ACE inhibitor by date, and local pollen counts by date. RESULTS: At Vanderbilt, the rate of angioedema was significantly associated with tree pollen months (P = .01 from χ(2) test). When separate analyses were conducted in patients with a history of seasonal allergies and patients without, the rate of ACE inhibitor-associated angioedema was increased during tree pollen months only in patients with a history of seasonal allergies (P = .002). In Marshfield, the rate of angioedema was significantly associated with ragweed pollen months (P = .025). In ONTARGET, a positive trend was observed between the ACE inhibitor-associated angioedema rate and grass season, although it was not statistically significant (P = .057). CONCLUSIONS: Patients with ACE inhibitor-associated angioedema are more likely to present with this adverse drug event during months when pollen counts are increased.

KRAS testing and epidermal growth factor receptor inhibitor treatment for colorectal cancer in community settings.

BACKGROUND: In metastatic colorectal cancer (mCRC), mutations in the KRAS gene predict poor response to EGF receptor (EGFR) inhibitors. Clinical treatment guidelines now recommend KRAS testing if EGFR inhibitors are considered. Our study investigates the clinical uptake and utilization of KRAS testing. METHODS: We included 1,188 patients with mCRCs diagnosed from 2004 to 2009, from seven integrated health care delivery systems with a combined membership of 5.5 million. We used electronic medical records and targeted manual chart review to capture the complexity and breadth of real-world clinical oncology care. RESULTS: Overall, 428 patients (36%) received KRAS testing during their clinical care, and 266 (22%) were treated with EGFR inhibitors. Age at diagnosis (P = 0.0034), comorbid conditions (P = 0.0316), and survival time from diagnosis (P < 0.0001) influence KRAS testing and EGFR inhibitor prescribing. The proportion who received KRAS testing increased from 7% to 97% for those treated in 2006 and 2010, respectively, and 83% of all treated patients had a KRAS wild-type genotype. Most patients with a KRAS mutation (86%) were not treated with EGFR inhibitors. The interval between mCRC diagnosis and receipt of KRAS testing decreased from 26 months (2006) to 10 months (2009). CONCLUSIONS: These findings show rapid uptake and incorporation of this predictive biomarker into clinical oncology care. IMPACT: In this delivery setting, KRAS testing is widely used to guide treatment decisions with EGFR inhibitors in patients with mCRCs. An important future research goal is to evaluate utilization of KRAS testing in other delivery settings in the United States.

Utilization of HER2 genetic testing in a multi-institutional observational study.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) expression is amplified in about 20% of breast cancer tumors, and evaluation of HER2 status should influence therapy selection. A critical gap in our knowledge is the real-world implementation of HER2 testing and its impact on treatment decisions for women diagnosed with breast cancer. OBJECTIVES: To assess use of HER2 testing, to describe characteristics of patients who do or do not receive HER2 testing, to describe which HER2 tests were used (fluorescence in situ hybridization or immunohistochemistry), and to evaluate trastuzumab use as a function of HER2 results. STUDY DESIGN: The population included 6460 women diagnosed with invasive breast cancer between 1999 and 2007 at 8 geographically distributed Cancer Research Network healthcare delivery systems in the United States. METHODS: Electronic records were used to identify patient and tumor characteristics and treatment with trastuzumab. Chart abstraction was performed for 400 women (50 per site) to identify receipt of HER2 testing and results. RESULTS: More than 90% of study participants received HER2 testing. Everyone who received trastuzumab had a HER2 test, and nearly all (>95%) who received trastuzumab had a positive HER2 test result recorded in their medical chart. Most (77%) eligible patients with a positive HER2 test result diagnosed after 2005 received trastuzumab. This study expands upon previous work in individual health plans. CONCLUSIONS: HER2 status has been successfully incorporated into medical practice to guide treatment decisions for breast cancer patients in diverse integrated healthcare delivery settings.

Validity of eight integrated healthcare delivery organizations' administrative clinical data to capture breast cancer chemotherapy exposure.

BACKGROUND: Cancer Research Network (CRN) sites use administrative data to populate their Virtual Data Warehouse (VDW). However, information on VDW chemotherapy data validity is limited. The purpose of this study was to assess the validity of VDW chemotherapy data. METHODS: This was a retrospective cohort study of women ≥18 years with incident, invasive breast cancer diagnosed between January 1999 and December 2007. Pharmacy and procedure chemotherapy data were extracted from each site's VDW. Random samples of 50 patients stratified on trastuzumab, anthracyclines, and no chemotherapy exposure was selected from each site for detailed chart abstraction. Weighted sensitivities and specificities of VDW compared with abstracted data were calculated. Cumulative doses calculated from VDW data were compared with doses obtained from the medical chart review. RESULTS: The cohort included 13,497 patients with 6,456 (48%) chart review eligible. Patients in the sample (N = 400) had a mean age of 65 years. Trastuzumab, anthracycline, and other chemotherapy weighted sensitivities were 95%, 97%, and 100%, respectively; specificities were 99%, 99%, and 93%, respectively; positive predictive values were 96%, 99%, and 55%, respectively; and negative predictive values were 99%, 96%, and 100%. Trastuzumab and anthracyclines VDW mean doses were 873 and 386 mg, respectively, whereas abstracted mean doses were 1,734 and 369 mgs, respectively (R(2) = 0.14, P < 0.01 and R(2) = 0.05, P = 0.03, respectively). CONCLUSIONS: Sensitivities and specificities for CRN chemotherapy VDW data were high and dosages were correlated with chart information. IMPACT: The findings support the use of CRN data in evaluating chemotherapy exposures and related outcomes.

Dietary intake in the Personalized Medicine Research Project: a resource for studies of gene-diet interaction.

BACKGROUND: To describe the dietary intake of participants in the Personalized Medicine Research Project (PMRP), and to quantify differences in nutrient intake by smoking status and APOE4-a genetic marker that has been shown to modify the association between risk factors and outcomes. METHODS: The PMRP is a population-based DNA, plasma and serum biobank of more than 20,000 adults aged 18 years and older in central Wisconsin. A questionnaire at enrollment captures demographic information as well as self-reported smoking and alcohol intake. The protocol was amended to include the collection of dietary intake and physical activity via self-reported questionnaires: the National Cancer Institute 124-item Diet History Questionnaire and the Baecke Physical Activity Questionnaire. These questionnaires were mailed out to previously enrolled participants. APOE was genotyped in all subjects. RESULTS: The response rate to the mailed questionnaires was 68.2% for subjects who could still be contacted (alive with known address). Participants ranged in age from 18 to 98 years (mean 54.7) and 61% were female. Dietary intake is variable when comparing gender, age, smoking, and APOE4. Over 50% of females are dietary supplement users; females have higher supplement intake than males, but both have increasing supplement use as age increases. Food energy, total fat, cholesterol, protein, and alcohol intake decreases as both males and females age. Female smokers had higher macronutrient intake, whereas male nonsmokers had higher macronutrient intake. Nonsmokers in both genders use more supplements. In females, nonsmokers and smokers with APOE4 had higher supplement use. In males, nonsmokers with APOE4 had higher supplement use between ages 18-39 only, and lower supplement use at ages above 39. Male smokers with APOE4 had lower supplement use. CONCLUSION: Dietary intake in PMRP subjects is relatively consistent with data from the National Health and Nutrition Examination Survey (NHANES). Findings suggest a possible correlation between the use of supplements and APOE4. The PMRP dietary data can benefit studies of gene-environment interactions and the development of common diseases.

Vitamin E supplementation and cataract: randomized controlled trial.

OBJECTIVE: To determine whether treatment with vitamin E (500 IU daily) reduces either the incidence or rate of progression of age-related cataracts. DESIGN: A prospective, randomized, double-masked, placebo-controlled clinical trial entitled the Vitamin E, Cataract and Age-Related Maculopathy Trial. PARTICIPANTS: Of 1906 screened volunteers, 1193 eligible subjects with early or no cataract, aged 55 to 80 years, were enrolled and followed up for 4 years. INTERVENTION: Subjects were assigned randomly to receive either 500 IU of natural vitamin E in soybean oil encapsulated in gelatin or a placebo with an identical appearance. MAIN OUTCOME MEASURES: The incidence and progression rates of age-related cataract were assessed annually with both clinical lens opacity gradings and computerized analysis of Scheimpflug and retroillumination digital lens images obtained with a Nidek EAS-1000 lens camera. The analysis was undertaken using data from the eye with the more advanced opacity for each type of cataract separately and for any cataract changes in each individual. RESULTS: Overall, 87% of the study population completed the 4 years of follow-up, with 74% of the vitamin E group and 76% of the placebo group continuing on their randomized treatment allocation throughout this time. For cortical cataract, the 4-year cumulative incidence rate was 4.5% among those randomized to vitamin E and 4.8% among those randomized to placebo (P = 0.87). For nuclear cataract, the corresponding rates were 12.9% and 12.1% (P = 0.77). For posterior subcapsular cataract, the rates were 1.7% and 3.5% (P = 0.08), whereas for any of these forms of cataract, they were 17.1% and 16.7%, respectively. Progression of cortical cataract was seen in 16.7% of the vitamin E group and 18.4% of the placebo group (P = 0.76). Corresponding rates for nuclear cataract were 11.4% and 11.9% (P = 0.84), whereas those of any cataract were 16.5% and 16.7%, respectively. There was no difference in the rate of cataract extraction between the 2 groups (P = 0.87). Lens characteristics of the participants withdrawn from the randomized medications were not different from those who continued. CONCLUSIONS: Vitamin E given for 4 years at a dose of 500 IU daily did not reduce the incidence of or progression of nuclear, cortical, or posterior subcapsular cataracts. These findings do not support the use of vitamin E to prevent the development or to slow the progression of age-related cataracts.

Eye health in rural Australia.

A review of the current literature relating to eye health in rural Australia was conducted. Few studies have been undertaken, with most information provided by the Australian Institute of Health and Welfare databases, The National Trachoma and Eye Health Program of 1980 and the Visual Impairment Project in Victoria in the mid 1990s. Key findings were that the rural population has an increased prevalence of pterygium, cataract, ocular trauma and glaucoma, but no difference in refractive error or diabetic retinopathy (although data are limited). Rural residents are more likely to have seen an optometrist but less likely to have seen an ophthalmologist. Interventions have been undertaken in ophthalmologist training to increase the rural workforce and tele-ophthalmology to provide city-based metropolitan ophthalmological support for rural practitioners. Further epidemiological data and evaluated interventions are urgently required to help identify and address the needs of rural Australian communities.

Vitamin E supplementation and macular degeneration: randomised controlled trial.

OBJECTIVE: To determine whether vitamin E supplementation influences the incidence or rate of progression of age related maculopathy (AMD). DESIGN: Prospective randomised placebo controlled clinical trial. SETTING: An urban study centre in a residential area supervised by university research staff. PARTICIPANTS: 1193 healthy volunteers aged between 55 and 80 years; 73% completed the trial on full protocol. INTERVENTIONS: Vitamin E 500 IU or placebo daily for four years. PRIMARY OUTCOME: development of early age related macular degeneration in retinal photographs. Other measures included alternative definitions of age related macular degeneration, progression, changes in component features, visual acuity, and visual function RESULTS: The incidence of early age related macular degeneration (early AMD 3) was 8.6% in those receiving vitamin E versus 8.1% in those on placebo (relative risk 1.05, 95% confidence interval 0.69 to 1.61). For late disease the incidence was 0.8% versus 0.6% (1.36, 0.67 to 2.77). Further analysis showed no consistent differences in secondary outcomes. CONCLUSION: Daily supplement with vitamin E supplement does not prevent the development or progression of early or later stages of age related macular degeneration.