Katrina Armstrong

Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.Rationale: Genetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EGAPP Working Group (EWG) constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. We found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.Analytic Validity: The EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.Clinical Validity: After accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section).Clinical Utility: The EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate.Contextual Issues: CRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.

Barriers to influenza immunization in a low-income urban population

BACKGROUND Although influenza immunization significantly reduces mortality from influenza, over one third of elderly Americans are not immunized each year. Low rates of immunization are particularly concerning among African-American low-income populations. Preliminary interviews suggested that fear of undisclosed ingredients in the influenza vaccine may impede vaccine acceptance in this vulnerable population. OBJECTIVES To assess the role of concern about vaccine contents and other factors in the use of influenza immunization among a predominantly African-American low-income urban population. METHODS Cross-sectional, health-system-population-based, telephone survey of a random sample of West Philadelphia residents aged > or =65 years. RESULTS Of 659 eligible individuals, 486 (73.8%) were successfully interviewed. Concern about undisclosed shot contents was reported by 132 (20%) respondents and was inversely associated with vaccine receipt (OR 0. 49, 95% CI 0.26-0.91). This association was similar among African Americans and Caucasians. In addition, receipt of influenza vaccine was inversely associated with belief that immunization is inconvenient (OR 0.14, 95% CI 0.05-0.36), belief that immunization is painful (OR 0.21, 95% CI 0.08-0.54), and history of previous side effects (OR 0.33, 95% CI 0.18-0.60), and positively associated with physician recommendation (OR 3.22, 95% CI 1.76-5.93). CONCLUSIONS In a low-income urban population, concern about undisclosed vaccine contents appears to impede acceptance of influenza immunization among both African Americans and Caucasians. Directly addressing this concern offers a new approach to increasing immunization in this vulnerable population.

Screening mammography in women 40 to 49 years of age: a systematic review for the American College of Physicians.

Key Summary Points Meta-analyses of randomized, controlled trials demonstrate a 7% to 23% reduction in breast cancer mortality rates from screening mammography in women 40 to 49 years of age. Screening mammography is associated with an increased risk for mastectomy but a decreased risk for adjuvant chemotherapy and hormone therapy. The risk for radiation is small (30 to 200 breast cancer deaths occurred in an annual screening of 100000 women 40 to 49 years of age). Rates of false-positive mammograms are high (20% to 56% after 10 mammograms), but false-positive results have little effect on psychological health or subsequent mammography adherence. Although many women report pain at the time of mammography, few see pain as a deterrent to future screening. Breast cancer risk varies among women in their 40s and affects the absolute reduction in rates of breast cancer mortality and the absolute risk for false-positive results on screening mammography. Several decades after the first guidelines for breast cancer screening were published, the routine use of mammography among asymptomatic women remains a topic of considerable debate (1, 2). This debate surfaces occasionally on screening women 50 years of age or older but persists regularly for screening women in their 40s (3, 4). The persistence of this controversy suggests a level of unease with our current understanding of the benefits and risks of mammography and with how this understanding has been translated into screening recommendations. Understanding the risks and benefits of screening mammography among women in their 40s is important because of the critical position that breast cancer holds in that age group. In the United States, breast cancer is one of the most common causes of death for women in their 40s. In 2002, almost 5000 women between 40 and 49 years of age died of breast cancer, compared with the 6800 women who died of heart disease or 1500 women who died of HIV (5). However, despite the relative importance of breast cancer in this age group, the burden of breast cancer among women in their 40s is low for a population-based screening program. More than 98% of women will not develop breast cancer between 40 and 50 years of age, but they will be subject to the risks of population-based screening. Of the 44000 women who die of breast cancer each year, fewer than one fifth received their diagnoses between the ages of 40 and 49 years (6, 7). We describe the results of a systematic review of the benefits and risks for screening mammography among women 40 to 49 years of age. Currently, 8 published meta-analyses discuss the effect of mammography screening in women 40 to 49 years of age on breast cancer mortality rates (816). All but 1 demonstrate a reduction in mortality rates from screening mammography. Thus, we did not perform another meta-analysis of the effect of screening mammography on breast cancer mortality rates, but we reviewed briefly the benefits of mammography screening derived from published screening trials and meta-analyses. In addition, we focused on 2 areas that are less well-studied but may affect recommendations about screening mammography among women in this age group: 1) risks of mammography screening and 2) variation in the risks and benefits of mammography according to an individual womans characteristics. Methods Data Sources We created a framework of the potential risks and benefits of screening mammography to guide the literature search (Figure). On the basis of the framework, we searched MEDLINE, Pre-MEDLINE, and the Cochrane Central Register of Controlled Trials for English-language publications. We conducted the initial searches in spring 2004 and updated them in May 2005. General search strategies included Medical Subject Headings (MeSH) terms mammography or breast neoplasms and mass screening, as well as the keywords mammography, screening, and breast cancer. We conducted additional searches for each individual risk or benefit by using appropriate keywords and MeSH terms. We reviewed the references of all selected articles to identify additional relevant articles. Figure. Risks and benefits of screening mammography. Numbers correspond to the risks and benefits outlined in the Table. Study Selection Although previous systematic reviews have largely focused on randomized, controlled trials of mammography screening to quantify the benefit of screening on breast cancer mortality rates, most evidence about risks and other benefits of mammography is derived from observational studies, primarily prospective cohort studies (Table). Thus, we included a wide range of study designs in our review, with the included studies depending on the question and the available evidence. We used meta-analyses to assess the effect of mammography screening on breast cancer mortality rates and the risk for a false-positive mammogram at a single screening; randomized, controlled trials and prospective cohort studies to assess the effect of mammography on breast cancer treatment and the cumulative risk for a false-positive mammogram; and both prospective and cross-sectional observational studies to assess the other risks of mammography. We excluded case series and ecological designs for all risks except for ductal carcinoma in situ (DCIS), because most published data on DCIS outcomes are derived from these study designs. In addition, we reviewed the available publications from the 8 original mammography trials and the published simulation models of the effect of radiation from mammography screening. When possible, we focused on evidence from studies of screening mammography in women in their 40s or analyses of this age group within larger cohorts. When this was not possible, we used studies of screening mammography in older women. In the case of multiple publications from the same study, we included only the most recent publication in our analysis. Table. Risks and Benefits of Screening Mammography For study selection, a study investigator reviewed abstracts of all primary research articles to determine whether the full-text article should be retrieved. We retrieved 873 full-text articles, and 2 investigators reviewed them. In addition to the publications from the original trials, 117 of these articles met inclusion criteria. Data Extraction and Quality Assessment Two investigators abstracted information about the study design, setting, study sample, measures, analysis, and results. When needed, we contacted authors to clarify questions about study design or results. We evaluated study quality by using the approach proposed by the Centre for Evidence-Based Medicine (www.cebm.net/levels_of_evidence.asp) (Appendix Table 1). The lead investigator adjudicated any disagreements between the reviewers about article content and quality. Appendix Table 1. Evidence-Based Medicine Review Score: Criteria Used to Assess Study Quality* Role of the Funding Source The review was conducted under contract with the American College of Physicians. The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the article for publication. Results Benefits Breast Cancer Mortality Many meta-analyses have combined the results of major mammography screening trials to assess the effect of screening on breast cancer mortality rates. The latest meta-analysis demonstrated that screening mammography every 1 to 2 years in women 40 to 49 years of age results in a 15% decrease in breast cancer mortality after 14 years of follow-up (relative risk, 0.85 [95% CI, 0.73 to 0.99]) (12). This effect size is very similar to that reported by most previous meta-analyses of women 40 to 49 years of age (8, 10, 13, 14, 16). It is smaller than the 22% reduction seen among women 50 years of age or older (relative risk, 0.78 [CI, 0.70 to 0.87]) (12). The meta-analysis did not include the recently published results of the United Kingdom trial of annual mammography screening in 160921 women in their 40s (relative risk, 0.83 [CI, 0.66 to 1.04]) (17). However, this estimate is so similar to the results of the meta-analyses that the findings are unlikely to substantively change. Nevertheless, the effect of mammography screening on breast cancer mortality rates for women in their 40s remains controversial for several reasons. These reasons include concern about the quality of the trials that found mammography to have the largest benefit, the interval until the mortality rate reduction began, and the validity of death due to breast cancer as the primary end point (2). We review each issue in the following sections. Study quality is important because high-quality studies are more likely to provide accurate estimates of the effect size. However, judging study quality is difficult because of imperfect reporting and lack of consensus on criteria for evaluating studies. Furthermore, high-quality studies are relatively uncommon. In the setting of screening mammography for women 40 to 49 years of age, previous meta-analyses differ in their assessment of study quality and study inclusion. The Cochrane meta-analysis (2) excluded all but 2 of the 8 trials that provided information about this age group (the Canadian trial and the Malm trial). The most recent meta-analysis, which was from the U.S. Preventive Services Task Force (12), included all trials but the Edinburgh trial. Other meta-analyses have included all 8 trials (10, 11, 13, 14, 16). To a great extent, these differences arise from different levels of concern about inadequate or inconsistent information in study publications, including variation in the numbers of participants in sequential reports; differences in baseline characteristics among groups; and lack of information about randomization procedures, date of trial entry, and other study characteristics. Although many of these concerns cannot be fully resolved, recent analyses and critical reviews support the argument that none of the trials is suf

Content of Weblogs Written by Health Professionals

BackgroundMedical weblogs (“blogs”) have emerged as a new connection between health professionals and the public.ObjectiveTo examine the scope and content of medical blogs and approximate how often blog authors commented about patients, violated patient privacy, or displayed a lack of professionalism.DesignWe defined medical blogs as those that contain some medical content and were apparently written by physicians or nurses. We used the Google search term “medical blog” to begin a modified snowball sampling method to identify sites posting entries from 1/1/06 through 12/14/06. We reviewed five entries per blog, categorizing content and characteristics.ResultsWe identified 271 medical blogs. Over half (56.8%) of blog authors provided sufficient information in text or image to reveal their identities. Individual patients were described in 114 (42.1%) blogs. Patients were portrayed positively in 43 blogs (15.9%) and negatively in 48 blogs (17.7%). Of blogs that described interactions with individual patients, 45 (16.6%) included sufficient information for patients to identify their doctors or themselves. Three blogs showed recognizable photographic images of patients. Healthcare products were promoted, either by images or descriptions, in 31 (11.4%) blogs.ConclusionsBlogs are a growing part of the public face of the health professions. They offer physicians and nurses the opportunity to share their narratives. They also risk revealing confidential information or, in their tone or content, risk reflecting poorly on the blog authors and their professions. The health professions should assume some responsibility for helping authors and readers negotiate these challenges.

Racial/Ethnic Differences in Physician Distrust in the United States

OBJECTIVES We examined the racial/ethnic and geographic variation in distrust of physicians in the United States. METHODS We obtained data from the Community Tracking Study, analyzing 20 sites where at least 5% of the population was Hispanic and 5% was Black. RESULTS In univariate analyses, Blacks and Hispanics reported higher levels of physician distrust than did Whites. Multivariate analyses, however, suggested a complex interaction among sociodemographic variables, city of residence, race/ethnicity, and distrust of physician. In general, lower socioeconomic status (defined as lower income, lower education, and no health insurance) was associated with higher levels of distrust, with men generally reporting more distrust than women. But the strength of these effects was modified by race/ethnicity. We present examples of individual cities in which Blacks reported consistently higher mean levels of distrust than did Whites, consistently lower mean levels of distrust than did Whites, or a mixed relationship dependent on socioeconomic status. In the same cities, Hispanics reported either consistently higher mean levels of distrust relative to Whites or a mixed relationship. CONCLUSIONS Racial/ethnic differences in physician distrust are less uniform than previously hypothesized, with substantial geographic and individual variation present.

Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings

OBJECTIVE To determine long-term survival and predictors of recurrence in patients with platinum-treated ovarian cancer who were followed for 10 years after second-look laparotomy with negative findings. METHODS Records were reviewed of 91 consecutive patients with negative findings on second-look laparotomy after platinum-based chemotherapy between January 1978 and January 1987. Statistical analysis used Kaplan-Meier survival curves, Cox proportional hazards, and multiple logistic regression. RESULTS Mean age of patients was 57 (range 30-79) years. Distribution by stage and grade was as follows: stage I, ten; II, 18; III, 57; IV, six; grade 1, 18; 2, 28; 3, 45. Forty-seven of 91 women had optimal initial cytoreduction. Recurrence-free survival rates for all subjects were 75% at 2 years, 55% at 5 years, and 52% at 10 years. For women with stage I disease, the recurrence-free survival rate was 90% at 2, 5, and 10 years. For women with stage II disease, recurrence-free survival rates were 78, 72, and 66% at 2, 5, and 10 years, respectively. Patients with stage III or IV disease had recurrence-free survival rates of 72, 44, and 40% at 2, 5, and 10 years, respectively. Risk of recurrent disease was related to tumor stage (relative risk [RR] 2.02; 95% confidence interval [CI] 1.2, 3.3; P = .005), grade (RR 2.00; 95% CI 1.3, 3.2; P = .004), and presence of a residual tumor of more than 2 cm at the end of initial surgery (RR 3.19; 95% CI 1.2, 8.5; P = .02). CONCLUSION Ovarian cancer patients face an appreciable risk of recurrence in the first 5 years after second-look laparotomy with negative findings after platinum-based chemotherapy, but those who remain disease free at 5 years have excellent long-term survival rates. Tumor stage, grade, and presence of a residual tumor of more than 2 cm after initial surgery are significant predictors of recurrence.

Hormone Replacement Therapy and Life Expectancy After Prophylactic Oophorectomy in Women With BRCA1/2 Mutations: A Decision Analysis

PURPOSE The decision about prophylactic oophorectomy is difficult for many premenopausal women with BRCA1/2 mutations because of concerns and controversy about the use of hormone replacement therapy (HRT) after oophorectomy. PATIENTS AND METHODS A Markov decision analytic model used the most current epidemiologic data to assess the expected outcomes of prophylactic oophorectomy with or without HRT (to age 50 years or for life) in cohorts of women with BRCA1/2 mutations. Sensitivity analyses were conducted to assess the impact of alternative assumptions about effects of HRT, effects of prophylactic oophorectomy, and risks of cancer associated with BRCA1/2 mutations. RESULTS In our model, prophylactic oophorectomy lengthened life expectancy in women with BRCA1/2 mutations, irrespective of whether HRT was used after oophorectomy. This gain ranged from 3.34 to 4.65 years, depending on age at oophorectomy. Use of HRT after oophorectomy was associated with relatively small changes in life expectancy (+0.17 to -0.34 years) when HRT was stopped at age 50, but larger decrements in life expectancy if HRT was continued for life (-0.79 to -1.09 years). HRT was associated with a gain in life expectancy of between 0.39 and 0.79 years for mutation carriers undergoing both prophylactic mastectomy and oophorectomy. CONCLUSION On the basis of the results of this decision analysis, we recommend that women with BRCA1/2 mutations undergo prophylactic oophorectomy after completion of childbearing, decide about short-term HRT after oophorectomy based largely on quality-of-life issues rather than life expectancy, and, if using HRT, consider discontinuing treatment at the time of expected natural menopause, approximately age 50 years.

Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

This statement summarizes the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendations regarding CYP450 genetic testing in adult patients beginning treatment with selective serotonin reuptake inhibitors (SSRIs), and the supporting scientific evidence. EGAPP is a project developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice in the United States. A key goal of the EGAPP Working Group is to develop conclusions and recommendations regarding clinical genomic applications and to establish clear linkage to the supporting scientific evidence. The Working Group members are nonfederal experts in genetics, laboratory medicine, and clinical epidemiology convened to establish methods and processes; set priorities for review topics; participate in technical expert panels for commissioned evidence reviews; publish recommendations; and provide guidance and feedback on other project activities.Summary of Recommendation The EGAPP Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed.Rationale: The EGAPP Working Group found no evidence linking testing for CYP450 to clinical outcomes in adults treated with SSRIs. While some studies of a single SSRI dose in healthy patients report an association between genotypic CYP450 drug metabolizer status and circulating SSRI levels, this association was not supported by studies of patients receiving ongoing SSRI treatment. Further, CYP450 genotypes are not consistently associated with the patient outcomes of interest, including clinical response to SSRI treatment or adverse events as a result of treatment. No evidence was available showing that the results of CYP450 testing influenced SSRI choice or dose and improved patient outcomes, or was useful in medical, personal, or public health decision-making. In the absence of evidence supporting clinical utility, it is not known if potential benefits from CYP450 testing will outweigh potential harms. Potential harms may include increased cost without impact on clinical decision making or improvement in patient outcomes, less effective treatment with SSRI drugs, or inappropriate use of genotype information in the management of other drugs metabolized by CYP450 enzymes.

Symptom Burden Among Cancer Survivors: Impact of Age and Comorbidity

Background: Previous research among specific cancer populations has shown high but variable symptom burden; however, very little is known about its extent and pattern among the entire population of US cancer survivors, which is more clinically relevant to primary care physicians. Methods: To determine the prevalence of ongoing symptom burden among cancer survivors and compare it with the general population without cancer, we analyzed data from the 2002 National Health Interview Survey, which included 1,904 cancer survivors and 29,092 controls. Main outcome measures included self-reported ongoing pain, psychological distress, and insomnia. Multivariate logistic regression models were used to adjust for confounders and test for interactions. Results: The rates of ongoing pain, psychological distress, and insomnia among cancer survivors were 34%, 26%, and 30%, respectively, and were significantly higher (all P < .001) than controls without a history of cancer (18%, 16%, and 17%). Compared with controls in the same age groups, younger survivors (younger than 50) were much more likely to report ongoing symptoms than older survivors (older than 64); adjusted odds ratios were 2.96 and 1.36 for pain in the respective age groups (P < .001). Comorbidities also interact with cancer status and contribute to a marked increase in reports of ongoing symptom burden among cancer survivors, with a greater number of comorbidities leading to greater degree of symptom burden in a dose-dependent manner (P < .001). Conclusions: The symptom burden among cancer survivors on a population level is substantial and can be impacted by other comorbidities. Thus, engaging primary care physicians in the design, testing, and implementation of effective interventions is important to reduce the symptom burden among cancer survivors.

Development and Testing of the Health Care System Distrust Scale

AbstractBACKGROUND: Distrust of the health care system may be a significant barrier to seeking medical care, adhering to preventive health care and treatment regimens, and participating in medical research. OBJECTIVE: To describe the development and psychometric testing of an instrument (the Health Care System Distrust Scale) to measure distrust of the health care system. METHODS: Scale development involved 2 phases. In Phase 1, a pilot instrument was developed based on a conceptual model of health care-related distrust. Draft items were created using focus group sessions with members of the general public, literature review, and expert opinion. Draft items were pilot tested with 55 individuals waiting to be assigned to jury duty at the Municipal Court of Philadelphia. A priori, candidate items for elimination or revision included those with >5% missing data, extremely low or high interitem or item-total correlations, or those having a negative effect on the scale’s internal consistency. In Phase 2, we conducted a survey of 400 prospective jurors to assess the reliability and validity of the final scale scores. RESULTS: In Phase 1, a 10-item scale was constructed that included 4 items measuring honesty, 2 items measuring confidentiality, 2 items measuring competence, and 2 items measuring fidelity. The participants in Phase 2 had a mean age of 41 years. Forty-three percent were African-American, 45% white, and 4% Hispanic. Scores on the Health Care System Distrust scale ranged from 12 to 46 with a possible range from 10 to 50. The mean score was 29.4 with a standard deviation of 6.33. No item had over 5% missing data. Internal consistency (Cronbach’s α) was 0.75. Item-total correlations ranged from 0.27 to 0.57. Principal components analysis revealed 1 general component accounting for 32% of the variance. Nine of the variables had loadings higher than 0.40. As predicted, distrust of the health care system was higher among African Americans than whites and was inversely correlated with trust in personal physicians. CONCLUSIONS: Initial testing suggests that we developed an instrument with valid and reliable scores in order to measure distrust of the health care system. Future research is needed to evaluate the validity and reliability of the Health Care System Distrust scale among diverse populations. This instrument can facilitate the investigation of the prevalence, causes, and effects of health care system distrust in the United States.