Individual patient radiation dose tracking: Perceptions of radiographers in South Africa.

INTRODUCTION: Medical imaging examinations that make use of ionising radiation provide valuable information towards patient management. Literature suggests that there is a significant rise in the number of patient referrals for such examinations. The concept "individual patient radiation dose tracking" (IPRDT) is introduced to optimise radiation monitoring. Many countries across the globe explored and implemented methods to enhance and promote the justification and optimisation principles essential for patient radiation safety. In South Africa (SA), however, attention to IPRDT is limited. METHODS: A qualitative research design was employed. Radiographers in the Western Cape Province of SA were purposefully sampled for participation in one-on-one, semi-structured interviews. Thematic analysis was applied to the transcribed interview data. RESULTS: This paper presents a theme developed from the radiographer cohort of ten (10) participants. The theme: the need for creating awareness and implementing legislative support structures, was developed from the data, with the following supporting subthemes: 1) stakeholder awareness and 'buy-in' 2) continuous professional development and 3) mandated practice. CONCLUSION: This study provides findings that are of value for patient radiation safety in SA by giving a voice to local stakeholders. Other countries that are conducting similar research investigations toward the integration of an IPRDT model, method, or framework, may also benefit from these findings. IMPLICATIONS FOR PRACTICE: The effective integration of IPRDT into the clinical environment requires unison amongst the relevant stakeholders and clarity on the various professionals' roles and responsibilities. The findings of this study furthermore suggest the involvement of regulatory organisations for the provision of a mandated form of practice at national and international levels.

One in four people may develop symptomatic hip osteoarthritis in his or her lifetime.

OBJECTIVE: To estimate the lifetime risk of symptomatic hip osteoarthritis (OA). DESIGN: We analyzed data from the Johnston County Osteoarthritis Project [a longitudinal population-based study of OA in North Carolina, United States (n=3068)]. The weighted baseline sample comprised 18% blacks and 54% women, and the mean age was 63 years (range=45-93). Symptomatic hip OA was defined as a Kellgren-Lawrence (K-L) radiographic score of ≥ 2 (anterior-posterior pelvis X-rays) and pain, aching or stiffness on most days, or groin pain, in the same hip. Lifetime risk, defined as the proportion who developed symptomatic hip OA in at least one hip by age 85, among people who live to age 85, was modeled using logistic regression with repeated measures (through generalized estimating equations). RESULTS: Lifetime risk of symptomatic hip OA was 25.3% [95% confidence interval (CI)=21.3-29.3]. Lifetime risk was similar by sex, race, highest educational attainment, and hip injury history. We studied lifetime risk by body mass index (BMI) in three forms: at age 18; at baseline and follow-up; and at age 18, baseline and follow-up and found no differences in estimates. CONCLUSION: The burden of symptomatic hip OA is substantial with one in four people developing this condition by age 85. The similar race-specific estimates suggest that racial disparities in total hip replacements are not attributable to differences in disease occurrence. Despite increasing evidence that obesity predicts an increased risk of both hip OA and joint replacement, we found no association between BMI and lifetime risk.

Predictive tests for linked changes.

Mutations may confer a survival advantage to an organism and they can also reduce their fitness. In particular, we are interested in identifying correlated changes in genomic sequences. We consider the general situation where the observed characters at two genomic positions are summarized by an r x c contingency table. The test statistic focusses on double departures from the consensus configuration. When the original data are aggregated into two possible categories at each position (consensus vs non-consensus character), we obtain a 2 x 2 table to derive a test statistic that deals with the total number of double changes. Expected values and variances are predicted, under the assumption of independence, from table entries corresponding to single-mutation events. In some situations, the resulting tests are more powerful than those previously proposed.

Design of vaccine equivalence/non-inferiority trials with correlated multiple binomial endpoints.

Immunogenicity trials that study the immune responses to vaccination are often used in the vaccine development process as alternatives to clinical efficacy trials. The comparisons of immune responses among various treatment groups are conducted in a non-inferiority or equivalence framework. When there exists a level of immune response that correlates with protection against disease, it is of interest to compare the proportion of responders as defined as response above a specific level or as a predefined increase in immune levels for post-vaccination levels above pre-vaccination levels. Since vaccines often contain several antigens, the correlations between the immune responses need to be taken into account in the analysis. In this paper, we describe appropriate testing methods for demonstrating the non-inferioritylequivalence of two treatments on each of the binomial endpoints. We conduct a comprehensive simulation study to shed light on how the Type I error and power are affected and to what extent when correlated multiple binomial endpoints are present in the vaccine trials. We also illustrate the computation of power for assessment of non-inferioritylequivalence in real studies.

Are American College of Rheumatology 50% response criteria superior to 20% criteria in distinguishing active aggressive treatment in rheumatoid arthritis clinical trials reported since 1997? A meta-analysis of discriminant capacities.

OBJECTIVE: To carry out a meta-analysis designed to compare the discriminant capacities of American College of Rheumatology 50% (ACR50) with 20% (ACR20) responses in clinical trials on rheumatoid arthritis reported after 1997 and to analyse whether ACR50 can be as informative as ACR20 in distinguishing active from control treatments in more recent trials. METHODS: Clinical trials on rheumatoid arthritis reported since 1997 were identified, which included aggressive combinations of disease-modifying antirheumatic drugs and glucocorticoids, as well as powerful new agents-leflunomide, etanercept, infliximab, anakinra, adalimumab, abatacept, tacrolimus and rituximab. A meta-analysis of ACR20 compared with ACR50 responses for 21 clinical trials was carried out on differences in proportions of responders for active and control treatments and corresponding odds ratios (ORs). RESULTS: In all but one clinical trial on rheumatoid arthritis published since 1997 with data available on ACR20 and ACR50, more than 50% of patients who were ACR20 responders among those randomised to active treatment were also ACR50 responders. This phenomenon was seen for control groups in 38% of trials, many of which included treatment with methotrexate. A meta-analysis of the clinical trials indicated a slight advantage to ACR50 for quantifying treatment comparisons, not significant for differences in proportions but significant for ORs. CONCLUSION: ACR20 and ACR50 seem to be similar in distinguishing active from control treatments in clinical trials on rheumatoid arthritis reported since 1997. As ACR50 represents a considerably stronger clinical response, ACR50 may be a preferred end point for contemporary clinical trials on rheumatoid arthritis.

A longitudinal study of the association between tooth loss and age-related hearing loss.

The purpose of this study was to investigate cross-sectional and longitudinal associations between hearing acuity and tooth loss in 1156 US veterans taking part in the Veterans Affairs' Normative Aging (NAS) and Dental Longitudinal (DLS) Studies in the Boston, MA, area. The mean age was 48 years (SD = 8.9), 5.3% were edentulous, and 15.4% had < 17 teeth at baseline. Hearing acuity was determined by puretone, air- and bone-conduction audiometry, and speech discrimination tests at triennial examinations over a 20-year follow-up period. Hearing decline was defined as a change from baseline in the average puretone air-conduction thresholds of > or = 20 dB at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz. The explanatory variables of interest were change since baseline in dentate status (cut points at < 1, < 17, and < 20 teeth), and in the number of teeth lost (linear). Linear and logistic regression models--which controlled for baseline audiological status, age, air-bone gap, and otoscopic examination at current visit--showed that subjects who went from having > or = 17 to < 17 teeth had 1.64 times (95% CI, 1.24-2.17) as high odds of having hearing decline as those with no change in their dentate status. For every tooth lost since baseline, there was a 1.04 times as high odds (95% CI, 1.02-1.06) for hearing decline, when additional baseline and time-varying covariates were taken into account in the model.

Mediation in a family-directed program for prevention of adolescent tobacco and alcohol use.

BACKGROUND: Family Matters is a universal intervention designed to prevent adolescent tobacco and alcohol use through involvement of family members and by targeting family risk factors for tobacco and alcohol use. Previously reported findings suggest that the program reduced the prevalence of both adolescent smoking and drinking in the 12 months after program completion. This paper reports analyses conducted to identify the mediators through which the program influenced adolescent smoking and drinking. METHODS: One thousand fourteen adolescents ages 12 to 14 years and their families, identified by random-digit dialing, were entered into a randomized trial. Adolescents and their parents provided data by telephone for measuring mediator and behavioral variables at baseline, 3 months, and 12 months after program completion. Repeated-measures logistic regression with generalized estimating equations was used to assess mediation processes. RESULTS: The program resulted in statistically significant changes in several substance-specific aspects of the family, such as rule setting about tobacco and alcohol use. However, the intermediate family effects did not account for the program effects on adolescent behavior. CONCLUSIONS: The variables hypothesized to explain program effects were not identified by direct empirical examination.

Monitoring a clinical trial with multiple hypotheses concerning the treatment effect on a single primary endpoint.

In a number of clinical trials there is interest in testing more than one hypothesis concerning the treatment effect on a single primary endpoint. For instance, a sponsor of a trial to demonstrate that a test treatment (T) is non-inferior to an active control (R) may also be interested in showing that T is superior to R, if this is the case. Using the closed testing method for constructing tests of multiple hypotheses which control the multiple level of significance, we provide a framework for testing these hypotheses sequentially during a trial at pre-planned interim analyses.

Applying sample survey methods to clinical trials data.

This paper outlines the utility of statistical methods for sample surveys in analysing clinical trials data. Sample survey statisticians face a variety of complex data analysis issues deriving from the use of multi-stage probability sampling from finite populations. One such issue is that of clustering of observations at the various stages of sampling. Survey data analysis approaches developed to accommodate clustering in the sample design have more general application to clinical studies in which repeated measures structures are encountered. Situations where these methods are of interest include multi-visit studies where responses are observed at two or more time points for each patient, multi-period cross-over studies, and epidemiological studies for repeated occurrences of adverse events or illnesses. We describe statistical procedures for fitting multiple regression models to sample survey data that are more effective for repeated measures studies with complicated data structures than the more traditional approaches of multivariate repeated measures analysis. In this setting, one can specify a primary sampling unit within which repeated measures have intraclass correlation. This intraclass correlation is taken into account by sample survey regression methods through robust estimates of the standard errors of the regression coefficients. Regression estimates are obtained from model fitting estimation equations which ignore the correlation structure of the data (that is, computing procedures which assume that all observational units are independent or are from simple random samples). The analytic approach is straightforward to apply with logistic models for dichotomous data, proportional odds models for ordinal data, and linear models for continuously scaled data, and results are interpretable in terms of population average parameters. Through the features summarized here, the sample survey regression methods have many similarities to the broader family of methods based on generalized estimating equations (GEE). Sample survey methods for the analysis of time-to-event data have more recently been developed and implemented in the context of finite probability sampling. Given the importance of survival endpoints in late phase studies for drug development, these methods have clear utility in the area of clinical trials data analysis. A brief overview of methods for sample survey data analysis is first provided, followed by motivation for applying these methods to clinical trials data. Examples drawn from three clinical studies are provided to illustrate survey methods for logistic regression, proportional odds regression and proportional hazards regression. Potential problems with the proposed methods and ways of addressing them are discussed.

Non-parametric analysis of covariance for confirmatory randomized clinical trials to evaluate dose-response relationships.

In confirmatory randomized clinical trials that are designed to compare multiple doses of a test treatment with a control group and with one another, there are often statistical issues regarding compound hypotheses and multiple comparisons which need to be considered. In most cases the analysis plan needs a clear specification for the proposed order for conducting statistical tests (or for managing the overall significance level), which statistical methods will be used, and whether adjustment for covariates will be performed. There are several benefits of specifying non-parametric analysis of covariance (ANCOVA) for performing the primary confirmatory analyses. Only minimal assumptions are needed beyond randomization in the study design, whereas regression model based methods have assumptions about model fit for which departures may require modifications that are incompatible with a fully prespecified analysis plan. Non-parametric methods provide traditionally expected results of ANCOVA; namely, a typically small adjustment to the estimate for a treatment comparison (so as to account for random imbalance of covariates between treatment groups) and variance reduction for this estimate when covariates are strongly correlated with the response of interest. The application of non-parametric ANCOVA is illustrated for two randomized clinical trials. The first has a (3 x 4) factorial response surface design for the comparison of 12 treatments (that is, combinations of three doses of one drug and four doses of a second drug) for change in blood pressure; and the second example addresses the comparison of three doses of test treatment and placebo for time-to-disease progression. This clinical trial has comparisons among treatments made for a dichotomous criterion, Wilcoxon rank scores and averages of cumulative survival rates. In each example, the non-parametric covariance method provides variance reduction relative to its unadjusted counterpart.

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee.

OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as "better" or "much better" by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as "better" or "much better" by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.

Effect of vaccination by community pharmacists among adult prescription recipients.

BACKGROUND: Millions of doses of influenza vaccine are administered each year in the United States at nontraditional sites and by nontraditional vaccine providers. Pharmacists are increasingly becoming vaccine providers. OBJECTIVES: To measure association between availability of pharmacist-immunizers and immunization delivery to adult prescription recipients, and the relative contributions of various types of vaccine providers. RESEARCH DESIGN: Mailed survey in spring 1999, contrasting adults in urban Washington State, where pharmacists administer vaccines, to adults in urban Oregon, where pharmacists did not. SUBJECTS: Cluster sample based on October 1998 prescription records suggesting need for influenza vaccine, derived from 24 community pharmacies belonging to one pharmacy chain. MEASURES: Vaccination status and choice of vaccine provider. RESULTS: Influenza vaccination rates among respondents 65 years or older increased 4.7% more in Washington than in Oregon between 1997 and 1998 (P = 0.20). The net increase in influenza vaccination rate among younger respondents taking indicator medications for chronic diseases for which influenza vaccination is recommended was 10.6% (P = 0.05). Among respondents unvaccinated against influenza in 1997, the 1998 influenza vaccination rate was 34.7% in Washington, compared with 23.9% in Oregon (P = 0.01). CONCLUSIONS: Vaccine delivery by pharmacists is associated with higher rates of vaccination among those younger than 65 taking indicator medications medications for chronic diseases, as well as prescription recipients unvaccinated against influenza in the previous year.

The influence of a family program on adolescent tobacco and alcohol use.

OBJECTIVES: This study examined a family-directed program's effectiveness in preventing adolescent tobacco and alcohol use in a general population. METHODS: Adolescents aged 12 to 14 years and their families were identified by random-digit dialing throughout the contiguous United States. After providing baseline data by telephone interviews, they were randomly allocated to receive or not receive a family-directed program featuring mailed booklets and telephone contacts by health educators. Follow-up telephone interviews were conducted 3 and 12 months after program completion. RESULTS: The findings suggested that smoking onset was reduced by 16.4% at 1 year, with a 25.0% reduction for non-Hispanic Whites but no statistically significant program effect for other races/ethnicities. There were no statistically significant program effects for smokeless tobacco or alcohol use onset. CONCLUSIONS: The family-directed program was associated with reduced smoking onset for non-Hispanic Whites, suggesting that it is worthy of further application, development, and evaluation.

Prediction of cardiac mortality after myocardial infarction: the role of maximal treadmill stress echocardiography.

Patients frequently undergo low-level exercise treadmill testing after acute myocardial infarction (MI) and, in the absence of inducible ischemia, a maximal test several weeks later. This study examines 203 patients who had 2-dimensional echocardiography before and after a maximal Bruce protocol exercise treadmill test performed 4 to 6 weeks after MI. The subjects were followed for a mean of 43 months (range 1 to 77 months). Predictors of cardiac mortality by multivariate or univariate analysis included an ejection fraction < or =40%, diabetes, age > or=70 years, and ischemia by exercise echocardiography but not by electrocardiography. Therefore, standard electrocardiographic monitoring during exercise treadmill testing 6 weeks after MI fails to predict cardiac mortality. The addition of pre-exercise and post-exercise treadmill stress echocardiography to readily available clinical parameters identifies those patients at greatest risk for cardiac death (resting ejection fraction < or=40%) and detects residual exercise-induced ischemia that may be of additional prognostic value.

Biopharmaceutical statistics in a pharmaceutical regulated environment: past, present, and future.

The practice of statistics in the pharmaceutical industry has changed markedly over the last 25 years. This paper examines the evolution of clinical trial statistics in relationship to advances in statistical methodology and computational power as well as the changing regulatory environment. The current role of the biopharmaceutical statistician is assessed along with the drivers for future change.

State scholarship, loan forgiveness, and related programs: the unheralded safety net.

CONTEXT: In the mid-1980s, states expanded their initiatives of scholarships, loan repayment programs, and similar incentives to recruit primary care practitioners into underserved areas. With no national coordination or mandate to publicize these efforts, little is known about these state programs and their recent growth. OBJECTIVES: To identify and describe state programs that provide financial support to physicians and midlevel practitioners in exchange for a period of service in underserved areas, and to begin to assess the magnitude of the contributions of these programs to the US health care safety net. DESIGN: Cross-sectional, descriptive study of data collected by telephone, mail questionnaires, and through other available documents, (eg, program brochures, Web sites). SETTING AND PARTICIPANTS: All state programs operating in 1996 that provided financial support in exchange for service in defined underserved areas to student, resident, and practicing physicians; nurse practitioners; physician assistants; and nurse midwives. We excluded local community initiatives and programs that received federal support, including that from the National Health Service Corps. MAIN OUTCOME MEASURES: Number and types of state support-for-service programs in 1996; trends in program types and numbers since 1990; distribution of programs across states; numbers of participating physicians and other practitioners in 1996; numbers in state programs relative to federal programs; and basic features of state programs. RESULTS: In 1996, there were 82 eligible programs operating in 41 states, including 29 loan repayment programs, 29 scholarship programs, 11 loan programs, 8 direct financial incentive programs, and 5 resident support programs. Programs more than doubled in number between 1990 (n = 39) and 1996 (n = 82). In 1996, an estimated 1306 physicians and 370 midlevel practitioners were serving obligations to these state programs, a number comparable with those in federal programs. Common features of state programs were a mission to influence the distribution of the health care workforce within their states' borders, an emphasis on primary care, and reliance on annual state appropriations and other public funding mechanisms. CONCLUSIONS: In 1996, states fielded an obligated primary care workforce comparable in size to the better-known federal programs. These state programs constitute a major portion of the US health care safety net, and their activities should be monitored, coordinated, and evaluated. State programs should not be omitted from listings of safety-net initiatives or overlooked in future plans to further improve health care access. JAMA. 2000;284:2084-2092.

The Safe Dates program: 1-year follow-up results.

OBJECTIVES: An earlier report described desirable 1-month follow-up effects of the Safe Dates program on psychological, physical, and sexual dating violence. Mediators of the program-behavior relationship also were identified. The present report describes the 1-year follow-up effects of the Safe Dates program. METHODS: Fourteen schools were in the randomized experiment. Data were gathered by questionnaires in schools before program activities and 1 year after the program ended. RESULTS: The short-term behavioral effects had disappeared at 1 year, but effects on mediating variables such as dating violence norms, conflict management skills, and awareness of community services for dating violence were maintained. CONCLUSIONS: The findings are considered in the context of why program effects might have decayed and the possible role of boosters for effect maintenance.

Prognostic value of exercise echocardiography in women in the community setting.

Treadmill stress echocardiography was performed in 1,136 women with known or suspected coronary artery disease whose clinical course was then evaluated a mean of 33 months later (range 12 to 60). The strongest predictor of an adverse outcome was the presence of a resting or an exercise-induced wall motion abnormality.

Non-parametric covariance methods for incidence density analyses of time-to-event data from a randomized clinical trial and their complementary roles to proportional hazards regression.

The principal response criteria for many clinical trials involve time-to-event variables. Usual methods of analysis for this type of response criterion include product-limit estimators of cumulative survival for the treatment groups, (stratified) logrank tests to compare treatments, and proportional hazards regression models with treatment and relevant covariates. When adjustment for covariates is of some importance, the relative roles of these methods may be of some concern, particularly for confirmatory clinical trials which must provide convincing findings to regulatory agencies. Unadjusted methods may have lower power, but there are issues regarding adjustment for covariates that may be controversial. These issues include applicability of proportional hazards assumptions, whether the correct model has been specified, and whether there is parallelism between treatments for relationships with covariates. One way to address these issues is to use non-parametric analysis of covariance strategies with extensions to log incidence density estimation. The principal basis for this method is no association between covariates and treatment groups as provided by randomized assignment of patients to groups. The background theory and strategies for computation are described for this method. Aspects of its application are illustrated for a clinical trial with two treatment groups and 722 patients. The objective of analysis for this clinical trial is evaluation of treatment effects with and without adjustment for 22 a priori covariates and a stratification for three geographical regions.