Interferon-gamma (+874) T/A genotypes and risk of IFN-alpha-induced depression.

Depression is a frequent side effect of interferon (IFN)-alpha therapy of hepatitis C (HCV) and is of great relevance with regard to adherence, compliance, and premature therapy discontinuation. There are no reliable tests to identify patients-at-risk for the development of IFN-alpha induced depression. We retrospectively studied distribution of IFN-gamma (IFNG) (+874) T/A genotypes in 170 Caucasian HCV patients treated by IFN-alpha. Distribution of IFNG (+874) genotypes was different between depressed and not depressed subjects with more TA and less AA carriers among depressed than among not depressed subjects (P = 0.003). Carriers with at least one T allele were more frequent among depressed than among not depressed patients (P = 0.003). Our results suggest that presence of high producer (T) alleles might be a genetic risk factor for the development of IFN-alpha-induced depression. Assessment of IFNG (+874) genotypes might help to identify patients-at-risk for IFN-alpha-induced depression. IFNG and IFN-alpha transcriptionally induce indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine (KYN) pathway of tryptophan (TRY) metabolism. IFN-induced up-regulation of IDO triggers depression by shifting TRY metabolism from formation of serotonin to production of neuroactive kynurenines. TRY-KYN pathway might be a new target for pharmacological prevention and treatment of IFN-alpha-induced psychiatric complications.

The effect of a handwashing intervention on preschool educator beliefs, attitudes, knowledge and self-efficacy.

This paper describes the effect of a preschool hygiene intervention program on psychosocial measures of educators regarding handwashing and communicable pediatric disease. A cluster-randomized trial, with randomization at the level of the preschool, was run in 40 Jerusalem preschool classrooms. Eighty preschool educators participated. The program used a multipronged approach which included elements aimed at staff, children, parents, school nurses and the classroom environment. Frontal lectures by medical, epidemiological and educational experts, along with printed materials and experiential learning, were provided to staff. Responses from a validated survey instrument were used to build four scales for each respondent regarding beliefs, attitudes, self-efficacy and knowledge. The scales were built on a Likert-type 1-7 scale (1 = minimum, 7 = maximum). The effect of the intervention was tested using mixed model analysis of variance. Response was received from 92.5% of educators. Educators believed that handwashing could affect health (mean = 5.5, SD = 1.1), had high levels of self-efficacy (mean = 6.1, SD = 0.9) and had positive attitudes toward handwashing (mean = 5.7, SD = 1.2). Knowledge was affected by the intervention (intervention: mean = 6.2, SD = 0.7; control: mean = 5.8, SD = 0.8). The combination of positive attitudes toward handwashing among educators and the program's effectiveness in imparting knowledge helped to create a sustained social norm of handwashing among many children in disparate locations.

Strategies for diagnosing and treating suspected acute bacterial sinusitis: a cost-effectiveness analysis.

OBJECTIVE: Symptoms suggestive of acute bacterial sinusitis are common. Available diagnostic and treatment options generate substantial costs with uncertain benefits. We assessed the cost-effectiveness of alternative management strategies to identify the optimal approach. DESIGN: For such patients, we created a Markov model to examine four strategies: 1) no antibiotic treatment; 2) empirical antibiotic treatment; 3) clinical criteria-guided treatment; and 4) radiography-guided treatment. The model simulated a 14-day course of illness, included sinusitis prevalence, antibiotic side effects, sinusitis complications, direct and indirect costs, and symptom severity. Strategies costing less than 50,000 dollars per quality-adjusted life year gained were considered "cost-effective." MEASUREMENTS AND MAIN RESULTS: For mild or moderate disease, basing antibiotic treatment on clinical criteria was cost-effective in clinical settings where sinusitis prevalence is within the range of 15% to 93% or 3% to 63%, respectively. For severe disease, or to prevent sinusitis or antibiotic side effect symptoms, use of clinical criteria was cost-effective in settings with lower prevalence (below 51% or 44%, respectively); empirical antibiotics was cost-effective with higher prevalence. Sinus radiography-guided treatment was never cost-effective for initial treatment. CONCLUSIONS: Use of a simple set of clinical criteria to guide treatment is a cost-effective strategy in most clinical settings. Empirical antibiotics are cost-effective in certain settings; however, their use results in many unnecessary prescriptions. If this resulted in increased antibiotic resistance, costs would substantially rise and efficacy would fall. Newer, expensive antibiotics are of limited value. Additional testing is not cost-effective. Further studies are needed to find an accurate,low-cost diagnostic test for acute bacterial sinusitis.

The great tocolytic debate: some pitfalls in the study of safety.

The controversy surrounding the use of tocolytic agents has been raging for decades. Tocolytic drugs play a pivotal role in the prevention of preterm birth, which is the major cause of neonatal morbidity and mortality. Studies on the efficacy and safety of these drugs are of the utmost importance to many disciplines within the medical community. Unfortunately, many clinical decisions regarding tocolytic agents are based on incorrect information resulting from flawed studies. In this article we discuss the major design flaws common to many studies of tocolytic safety and in so doing explain some of the conflicting evidence regarding safety. Each of the two major types of study designs, preterm birth retrospective studies and prospective randomized trials, is associated with a serious flaw. Retrospective preterm birth studies give misleading and inconclusive results to the question of safety because of the use of incomplete cohorts. The inadequately sized prospective studies in the current literature lack the power to detect important clinical differences.

Assessment of side effects in patients with chronic hepatitis C receiving combination therapy.

The purpose of this descriptive study is to review the adverse effects of combination therapy, interferon alfa-2b and ribavirin, in a sample of patients with chronic hepatitis C who were part of a larger multi-center trial (Bonkovsky, 1999). The sample (n = 13) was drawn from one hepatology practice in the northeastern United States. This secondary analysis reported sums, frequencies, means, and standard deviations for the sample. Patients who received 600 mg ribavirin per day in addition to interferon alfa-2B (Arm A) showed a mean of 9.5 different types of side effects. Patients who received 1000-1200 mg of ribavirin in addition to interferon alfa-2B (Arm B) had a mean of 8.6 different types of side effects. The highest-ranking side effects were fatigue (92%), insomnia (85%), alopecia (69%), and arthralgia (62%). A secondary analysis of the entire data set is required before confidence can be placed in the findings. Implications for nursing practice include the need for creative strategies to reduce the effects of fatigue, insomnia, alopecia, and arthralgia in patients with chronic hepatitis C.

Florida's "truth" campaign: a counter-marketing, anti-tobacco media campaign.

The "truth" campaign was created to change youth attitudes about tobacco and to reduce teen tobacco use throughout Florida by using youth-driven advertising, public relations, and advocacy. Results of the campaign include a 92 percent brand awareness rate among teens, a 15 percent rise in teens who agree with key attitudinal statements about smoking, a 19.4 percent decline in smoking among middle school students, and a 8.0 percent decline among high school students. States committed to results-oriented youth anti-tobacco campaigns should look to Florida's "truth" campaign as a model that effectively places youth at the helm of anti-tobacco efforts.

Internal pilot studies I: type I error rate of the naive t-test.

When sample size is recalculated using unblinded interim data, use of the usual t-test at the end of a study may lead to an elevated type I error rate. This paper describes a numerical quadrature investigation to calculate the true probability of rejection as a function of the time of the recalculation, the magnitude of the detectable treatment effect, and the ratio of the guessed to the true variance. We consider both 'restricted' designs, those that require final sample size at least as large as the originally calculated size, and 'unrestricted' designs, those that permit smaller final sample sizes than originally calculated. Our results indicate that the bias in the type I error rate is often negligible, especially in restricted designs. Some sets of parameters, however, induce non-trivial bias in the unrestricted design.

Internal pilot studies II: comparison of various procedures.

The two-stage design involves sample size recalculation using an interim variance estimate. Stein proposed the design in 1945; biostatisticians recently have shown renewed interest in it. Wittes and Brittain proposed a modification aimed at greater efficiency; Gould and Shih proposed a similar procedure, but with a different interim variance estimate based on blinded data. We compare the power of Stein's original test, an idealized version of the Wittes-Brittain test, and a theoretical optimal test which can be approximated in practice. We also compare two procedures that control the conditional type I error rate given the actual final sample size: Gould and Shih's procedure and a newly proposed 'second segment' procedure. The comparison among the first three procedures indicates that the Stein test is, unexpectedly, the test of choice under the original design alternative, whereas the approximate-optimal and Wittes-Brittain procedures appear to have superior power for detecting smaller treatment differences. As between the latter two procedures, the second segment procedure is more powerful when many observations are likely to be taken after the interim resizing, whereas otherwise the Gould-Shih procedure is superior.

Insurance type and the transportation to emergency departments of patients with acute cardiac ischemia: the ACI-TIPI Trial Insurance Study.

The relationship of insurance type to treatment-seeking behavior (ie, the transportation to emergency departments of patients with symptoms suggestive of acute cardiac ischemia) was evaluated. The focus was on comparing patients belonging to a health maintenance organization (HMO) with patients who had indemnity insurance. Data were collected prospectively on 10,783 patients presenting to emergency departments of 10 adult care hospitals in the Eastern and Midwestern United States between April and December 1993 as part of a clinical trial. A total of 6,604 patients presented within 24 hours of symptom onset. Although these patients as a group had a wide range of demographic and clinical characteristics, persons belonging to an HMO and those with indemnity insurance were very similar. The main outcome measures were whether the patient was transported by ambulance and the duration of time from symptom onset to emergency department arrival. A hospital-matched sample of HMO-insured and indemnity-insured patients allowed multivariable regression: HMO membership was not associated with a different rate of ambulance use (odds ratio = 1.0; 95% confidence interval = 0.73, 1.35) or duration of time from symptom onset to emergency department presentation (6 minutes less, P = 0.8). HMO participation was not related to treatment-seeking behavior, as reflected by ambulance use and duration of time from symptom onset to emergency department arrival. However, studies of more constrained managed care organizations and of broader ranges of patients are needed.

Variation in mortality among seven hemodialysis centers as a quality indicator.

OBJECTIVES: To identify patient attributes that were associated with increased mortality; variables that were associated with process of care that were correlated with mortality; and outlier centers after adjustment for patient attributes. DESIGN: Standard interviews were conducted by trained nurses with all patients. Detailed information regarding primary renal diagnosis, comorbidity, and results of laboratory tests were obtained from the medical charts. The vital status of the patients was obtained from the records of each of the centers. We used the Cox hazard method to identify variables that correlated with a 1-year mortality. Centers with observed mortality exceeding the 95% confidence interval (CI95) of the expected probability of death were marked as outliers. SETTING: Seven dialysis centers located in large teaching hospitals in Israel. PATIENTS: The current study included patients > 16 years of age who had undergone hemodialysis > 4 weeks prior to the day of data collection. RESULTS: The study included 564 patients. Significant differences were found in patient demographics and process variables among the centers. The following variables correlated with mortality; diabetes (odds ratio [OR], 2.03; CI95, 1.28-3.21); ischemic heart disease (OR, 2.2; CI95, 1.39-3.49); each year of age (OR, 1.04; CI95, 1.02-1.06); each 1 g% of albumin (OR, 0.51; CI95, 0.30-0.86). The average observed mortality in all centers was 17.4%. After adjustment for casemix, one center showed excess mortality (24% observed compared to 15% expected after adjustment for patient attributes; CI95, 6.2-23.7). CONCLUSIONS: The ability to compare mortality rates among dialysis centers to detect possible quality outliers depends on thorough consideration of patient attributes and random variation.

Differences in quality of life among patients receiving dialysis replacement therapy at seven medical centers.

The purpose of this study is to investigate the variations in quality of life (QOL) among patients with end-stage renal disease (ESRD) who are receiving replacement therapy in several dialysis centers. This observational study includes interviews with nurses and data extraction from medical charts for all 680 adults who had been on dialysis therapy for more than 4 weeks in seven dialysis centers. By using multivariate analysis, we generated a model to explain the variance in QOL as measured by the QL index score (developed by Spitzer et al., J Chronic Dis 1981; 34:585-597) among patients pooled from all centers. The expected mean QL index score and 95% confidence interval were computed for each dialysis center. Centers with observed mean QL index scores outside of the expected confidence range were marked as possible outliers. We found the following patient attributes to be independently associated with QOL: age, education, occupation, and certain comorbidities (e.g., diabetes, stroke). After adjustment for case mix, we could identify four outlier centers. After further adjustment for albumin in serum, a possible process indicator, two centers were no longer considered as outliers. These findings indicate that the variance in QOL of ESRD patients at different centers is not entirely explained by known case-mix factors. Further research should explore whether such variations are related to dissimilarity in the process of care at different centers.

An application of the Zucker-Wittes modified ratio estimate statistic in the Post Coronary Artery Bypass Graft (CABG) clinical trial.

In the Post Coronary Artery Bypass Graft (POST CABG) clinical trial, the primary outcome is substantial worsening (i.e., narrowing of the lumen diameter) of the vein grafts upon comparison of the baseline and follow-up angiograms. The patients had one to five non-occluded vein grafts at entry, so there may be from one to five primary outcome responses per patient. A modified ratio estimate (MRE) statistic, as described previously by Zucker and Wittes, may be used to analyze data of this kind. In the present paper we propose a more powerful MRE statistic when the event rates and/ or intraclass correlations vary according to number of grafts per patient. We also adapt this statistic to the factorial treatment design of the POST CABG clinical trial.

Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment.

When treating individual patients, physicians may face difficulties using the evidence from center-based randomized control trials (RCTs) due to limitations in these studies generalizability. Therefore, they often perform their own "informal" tests of treatment effectiveness. Single patient ("N-of-1") trials provide a structured design for more rigorous assessment of medical treatments of chronic diseases, but are applied only to the index patient. We present a hierarchical Bayesian random effects model to combine N-of-1 studies to obtain an estimate of treatment effectiveness for the population and to use this population information to aid in the evaluation of an individual patient's trial results. The model's treatment effect estimates are adjustments between the population estimate and the individual's observed results. This adjustment is based upon the within-patient and between-patient heterogeneity. We demonstrate this patient-focused method using published data from 23 N-of-1 trial results comparing amitriptyline and placebo for the treatment of fibromyalgia.

Presentations of acute myocardial infarction in men and women.

OBJECTIVE: To assess the influence of gender on the likelihood of acute myocardial infarction (AMI) among emergency department (ED) patients with symptoms suggestive of acute cardiac ischemia, and to determine whether any specific presenting signs or symptoms are associated more strongly with AMI in women than in men. DESIGN: Analysis of cohort data from a prospective clinical trial. SETTING: Emergency departments of 10 hospitals of varying sizes and types in the United States. PATIENTS: Patients 30 years of age or older (n = 10,525) who presented to the ED with chest pain or other symptoms suggestive of acute cardiac ischemia. MEASUREMENTS AND MAIN RESULTS: The prevalence of AMI was determined for men and women, and a multivariable logistic regression model predicting AMI was developed to adjust for patients' demographic and clinical characteristics. AMI was almost twice as common in men as in women (10% vs 6%). Controlling for demographics, presenting signs and symptoms, electrocardiogram features, and hospital, male gender was a significant predictor of AMI (odds ratio [OR] 1.7; 95% confidence interval [CI] 1.4, 2.0). The gender effect was eliminated, however, among patients with ST-segment elevations on electrocardiogram (OR 1.1; 95% CI 0.7, 1.7) and among patients with signs of congestive heart failure (CHF) (OR 1.1; 95% CI 0.8, 1.5). Signs of CHF were associated with AMI among women (OR 1.9; 95% CI 1.4, 2.6) but not men (OR 1.0; 95% CI 0.8, 1.3). Among patients who presented to EDs with chest pain or other symptoms suggestive of acute cardiac ischemia, AMI was more likely in men than in women. Among women with ST-segment elevation or signs of CHF, however, AMI likelihood was similar to that in men with these characteristics.

Method for separating patient and procedural factors while analyzing interdepartmental differences in rates of surgical infections: the Israeli Study of Surgical Infection in Abdominal Operations.

The objective of this study was to develop a method for analyzing differences in the performance of hospitals with respect to outcome by separating patient factors from procedural factors. The setting included a prospective follow-up of a sample of 5571 patients undergoing all types of surgical procedures in general surgery departments of 11 hospitals (20 surgical departments) across Israel. Of these, 769 underwent surgery involving the opening of the bowel, and they are the subjects of this report. Our method consisted of a prospective follow-up by a nurse epidemiologist, including detailed clinical data from the day of admission to hospital discharge. Analysis was directed at identifying reasons for the observed variability in wound infections among departments. Observed rates were compared with "expected" rates calculated from a logistic model pooled over departments. An attempt was made to separate patient-inherent characteristics, such as age, sex, and diagnosis, from procedural factors, depicting the patient's experience during his hospitalization. Results indicated that the marked interdepartmental differences in the observed infection rates were not accounted for by differences in the "case mix" among departments. Procedural risk factors in this data set played the main role in explaining the observed variability among surgical departments. We conclude that the simple method presented here used the data pooled over departments to define the main risk determinants for infection in this data set. It separated intrinsic patient factors from procedural characteristics, and could be used in studies where the main interest is to compare institutions, and point at reasons behind the differences in outcomes.

Inference for the association between coefficients in a multivariate growth curve model.

This paper generalizes the work of Blomqvist (1977, Journal of the American Statistical Association 72, 746-749) on inference for the relationship between the individual-specific slope and the individual-specific intercept in a linear growth curve model. The paper deals with longitudinal data involving one or more response variables and irregular follow-up times, with each response variable postulated to follow a linear growth curve model. The problem considered is inference concerning the association between one growth curve coefficient and another--for example, the slope and intercept for a selected response variable, or the two slopes for two different response variables--after adjusting for all remaining coefficients among all of the response variables. An inferential approach based on the method of moments and an inferential approach based on maximum likelihood are described, and the asymptotic properties of these procedures are presented. Extensions of the methodology to allow polynomial growth curves and baseline covariates are outlined. The methodology is illustrated with a practical example arising from a clinical trial in lung disease.