Bayesian adaptive trial design in acute heart failure syndromes: moving beyond the mega trial.

Over the last 2 decades, early treatment for patients presenting with acute heart failure syndromes (AHFS) has changed very little. Despite strikingly different underlying disease pathophysiology, presenting signs and symptoms, and precipitants of AHFS, most patients are treated in a homogeneous manner with intravenous loop diuretics. Inhospital studies of new therapies have produced disappointingly neutral results at best. Patients continue to be enrolled in trials long after initial therapy, at a time when vital signs have improved, symptoms have changed, and initiating pathophysiologic processes, such as myocardial and renal injury, have already begun. The "one-size-fits-all" approach to inhospital AHFS trials have been recognized as one potential contributor to the disappointing trial results seen to date. Studies designed to tailor the therapeutic approach to ascertain which treatment modalities are most effective depending on patient phenotypes have not been previously conducted in AHFS because this objective is not traditional in clinical trial design. Utilizing Bayesian adaptive designs in trials of early AHFS provides an opportunity to personalize therapy within the constraints of clinical research. Bayesian adaptive design is increasingly recognized as an efficient method for obtaining valid clinical trial results. At its core, this approach uses existing information at the time of trial initiation, combined with data accumulating during the trial, to identify treatments most beneficial for specific patient subgroups. Based on accumulating evidence, the study then "adapts" its focus to critical differences between treatments within patient subgroups. Bayesian adaptive design is ideally suited for investigating complex, heterogeneous conditions such as AHFS and affords investigators the ability to study multiple treatment approaches and therapies in multiple patient phenotypes within a single trial, while maintaining a reasonable overall sample size. Identifying specific treatment approaches that safely improve symptoms and facilitate early discharge in patients who traditionally are admitted, often for prolonged periods of time, are necessary if we aim to reverse the disappointing trend in clinical trial results. In this study, AHFS clinical researchers and biostatisticians with expertise and experience in designing "personalized medicine" trials describe the development of a Bayesian adaptive design for an emergency department-based AHFS trial.

Missed opportunities for diagnosis and treatment of diabetes, hypertension, and hypercholesterolemia in a Mexican American population, Cameron County Hispanic Cohort, 2003-2008.

INTRODUCTION: Diabetes, hypertension, and hypercholesterolemia are common chronic diseases among Hispanics, a group projected to comprise 30% of the US population by 2050. Mexican Americans are the largest ethnically distinct subgroup among Hispanics. We assessed the prevalence of and risk factors for undiagnosed and untreated diabetes, hypertension, and hypercholesterolemia among Mexican Americans in Cameron County, Texas. METHODS: We analyzed cross-sectional baseline data collected from 2003 to 2008 in the Cameron County Hispanic Cohort, a randomly selected, community-recruited cohort of 2,000 Mexican American adults aged 18 or older, to assess prevalence of diabetes, hypertension, and hypercholesterolemia; to assess the extent to which these diseases had been previously diagnosed based on self-report; and to determine whether participants who self-reported having these diseases were receiving treatment. We also assessed social and economic factors associated with prevalence, diagnosis, and treatment. RESULTS: Approximately 70% of participants had 1 or more of the 3 chronic diseases studied. Of these, at least half had had 1 of these 3 diagnosed, and at least half of those who had had a disease diagnosed were not being treated. Having insurance coverage was positively associated with having the 3 diseases diagnosed and treated, as were higher income and education level. CONCLUSIONS: Although having insurance coverage is associated with receiving treatment, important social and cultural barriers remain. Failure to provide widespread preventive medicine at the primary care level will have costly consequences.

Determinants of third dose of diphtheria-tetanus-pertussis (DTP) completion among children who received DTP1 at rural immunization centres in Pakistan: a cohort study.

OBJECTIVE: In Pakistan, a high proportion of children fail to complete third dose of diphtheria-tetanus-pertussis (DTP3) after having received the first dose (DTP1). A cohort study was conducted to identify the factors predicting three doses of diphtheria-tetanus-pertussis (DTP3) completion among children who have received DTP1 at six centres of Expanded Programme on Immunization (EPI) in rural Pakistan. METHOD: We analyzed a cohort of mother-child pairs enrolled at DTP1 between November 2005 and May 2006 in the standard care group of a larger randomized controlled trial. Data were collected from mothers on a structured questionnaire at enrollment, and each child was followed up at clinic visits for 90 days to record dates of DTP2 and DTP3. Multivariable log-binomial regression analysis was performed to identify the independent predictors of DTP3 completion. RESULTS: Only 39% (149/378) of enrolled children completed DTP3 during the follow-up period. After adjusting for the centre of enrollment in multivariable analysis, DTP3 completion was higher among children who were < or =60 days old at enrolment [adjusted risk ratio (Adj. RR) 1.39, 95% confidence interval (CI): 1.06-1.82], who were living in a household with monthly household income >Rs. 3000 (US$ 50) (Adj. RR 1.76, 95% CI: 1.16-2.65), and who were living < or =10 min away from EPI centre (Adj. RR 1.31, 95% CI: 1.04-1.66). CONCLUSIONS: Interventions targeting childhood immunization dropouts should focus on bringing more children to EPI centres on-time for initial immunization. Relocation of existing EPI centres and creation of new EPI centres at appropriate locations may decrease the travel time to the EPI centres and result in fewer immunization dropouts.

Epidemiologic attributes of invasive non-typhoidal Salmonella infections in Michigan, 1995--2001.

OBJECTIVES: To determine: (1) the incidence of invasive salmonellosis, (2) the distribution of specific Salmonella serotypes associated with invasive disease, and (3) the role of demographic characteristics in invasive salmonellosis in Michigan. DESIGN: We conducted a cross-sectional study using laboratory-confirmed cases of salmonellosis reported to the Michigan Department of Community Health between 1995 and 2001. METHODS: Average annual incidences (AAIs) for invasive salmonellosis were computed, and Poisson regression analysis was used to model the association between demographic attributes and invasive salmonellosis. RESULTS: Of 6797 cases of salmonellosis, 347 (5.1%) were characterized as invasive having an AAI of 0.5/100000. A covariate-adjusted Poisson model showed children aged <1 year to be at higher risk for invasive salmonellosis compared to adults aged 40-49 years (rate ratio (RR) 8.98, 95% confidence interval (CI) 5.69-14.17). No significant differences were found between males and females (RR 1.02, 95% CI 0.83-1.26), African-Americans and Caucasians (RR 0.95, 95% CI 0.64-1.42), and urban and rural residents (RR 0.98, 95% CI 0.76-1.26). Among the most common serotypes associated with invasive salmonellosis (Heidelberg, Typhimurium, and Enteritidis), Salmonella serotype Heidelberg had the highest blood invasiveness ratio (15.79/100). CONCLUSIONS: Children aged <1 year, especially of minority groups, are at higher risk for invasive Salmonella infections. Invasive salmonellosis may be included in the differential diagnosis of acute bacterial infections in young children with positive stool cultures for Salmonella.

A registry-based study on the association between human salmonellosis and routinely collected parameters in Michigan, 1995-2001.

PURPOSE: Salmonella serotypes are among the most common bacterial causes of foodborne gastroenteritis in the United States, associated with approximately 1.4 million human illnesses annually. Studies on trends of the serotypes and host-related factors are necessary for the development of effective prevention plans for foodborne diseases caused by these pathogens. MATERIALS AND METHODS: To determine the epidemiologic trends of human infections with the most common Salmonella serotypes in Michigan, we analyzed cases of culture-confirmed salmonellosis at the Michigan Department of Community Health (MDCH) from 1995 to 2001. RESULTS: A total of 6797 cases were reported, with an average annual incidence per 100,000 population (AAI) of 9.9. Among cases for which information on Salmonella serotype were available (6292 cases), the most common serotypes were S. Typhimurium (1596 cases, 26%), followed by S. Enteritidis (1309, 22%), S. Heidelberg (466, 8%) and S. Newport (222, 4%). From 1998 to 2001, the incidence of S. Typhimurium and S. Enteritidis decreased significantly by 39% (95% confidence interval [CI], 49% to 26% decrease) and 32% (95% CI, 44% to 18% decrease) respectively. Whereas the incidence of S. Newport increased by 101% (95% CI, 25% to 225% increase) and S. Heidelberg remained stable. Infection with these serotypes frequently occurred in the summer months. As a group, infants had the highest AAI for all Salmonella serotypes (75.0), S. Typhimurium (21.9), S. Enteritidis (14.0), S. Heidelberg (5.4), and S. Newport (1.7). Among patients whose race was known, blacks had a significantly higher AAI compared to whites for S. Typhimurium (2.5 vs. 1.3; RR = 2.3, 95% CI, 1.6-3.3), S. Enteritidis (1.4 vs. 1.1; relative rate (RR) = 1.4; 95% CI, 1.1-1.6), S. Heidelberg (0.8 vs. 0.3; RR = 3.6; 95% CI, 2.8-4.6), and S. Newport (0.3 vs. 0.1; RR = 2.8; 95% CI, 1.9-4.2). Among patients whose ethnicity was known, Hispanics had a significantly higher AAI for S. Enteritidis compared to non-Hispanics (1.0 vs. 0.5; RR = 1.9; 95% CI, 1.2-3.0), but not different significantly for S. Typhimurium, S. Heidelberg, and S. Newport. CONCLUSION: This study revealed the emergence of S. Newport and the high incidence of the most common Salmonella serotypes among infants, people of African descent, and Hispanics. This information can be used by the state and local health departments of Michigan to enhance salmonellosis prevention efforts by rationalizing the allocation of appropriate public health resources and personnel.

Demographic risk factors and incidence of Salmonella enteritidis infection in Michigan.

Salmonella Enteritidis is a major cause of foodborne disease worldwide. In the United States, this serotype has been associated with significant morbidity and mortality accounting for about 17% of all human Salmonella infections. Data on risk factors associated with serotype-specific Salmonella infections have not been reported in Michigan before. We carried out this study using surveillance data to identify high-risk groups and regions for S. Enteritidis infection in Michigan. Results of this study may be used to develop better control and prevention measures against this common foodborne pathogen. We analyzed data on Salmonella infections collected by the Michigan Department of Community Health's surveillance system (1995-2001). We computed age, gender, and place of residence-specific incidences of S. Enteritidis infection in Michigan using population-based denominators. We used Poisson regression analysis to study the associations between S. Enteritidis infection and certain predictor demographic variables, while controlling for confounders and covariates. We found an overall 1.87/100,000 average annual S. Enteritidis incidence with 1.91/100,000 in females and 1.81/100,000 in males. A higher incidence of S. Enteritidis infection was associated with Michigan children<5 years old when compared with average national estimates (p<0.01). The final adjusted Poisson model revealed that children<1 year of age [RR: 9.75, CI: 7.99-11.90] and children 1-4 years of age [RR: 3.37, CI: 2.83-4.02] are at higher risk for S. Enteritidis infection compared to adults aged 15-39 years. No significant differences in incidence of S. Enteritidis infections were found between urban and rural dwellers or between genders (p>0.05). The incidence rate of S. Enteritidis infection in the Michigan pediatric population (<5 years) was found to be significantly higher than average national estimates, meriting immediate public health attention. Risk factors for S. Enteritidis infection in Michigan children should be identified in order to devise effective control and prevention measures.

Update on statistical power and sample size assessments for cost-effectiveness studies.

Traditionally, competing healthcare interventions have been compared on their efficacy or effectiveness through clinical trials or epidemiological studies. Computation of sample size and/or statistical power for a proposed study to assess the relative effectiveness of two treatments is central to planning a good study. Economic evaluation studies focus on an additional dimension by comparing these interventions with respect to their cost. With rising healthcare costs and constrained budgets, these studies are increasingly being performed to ascertain which interventions can deliver additional health benefits at a reasonable cost. The design of a cost-effectiveness study for two competing treatments will require assessments of statistical power and sample size in demonstrating both effectiveness and/or cost-effectiveness. If the level of effectiveness of one treatment is known from a clinical trial, the next step is to assess its cost-effectiveness. In other circumstances, an investigator may wish to design a study that simultaneously assesses both effectiveness and cost-effectiveness. Statistical methodologies that have been proposed to address these issues are reviewed.