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CPCRA Methodological/Ancillary ArticlesDownload the complete list of CPCRA Methodological/Ancillary Articles as a PDF File Rouff J, Child C. Application of quality improvement theory and process in a national multicenter HIV/AIDS clinical trials network. Qual Manag Health Care 2003;12(2):89-96.
Effective clinical trials depend on the production of scientifically sound data. Clinical research coordinators monitor various activities to assure that data meet standards for timeliness and quality. Traditional methods of assuring data quality are less than optimal because they are based on correcting mistakes after they occur. Because they are focused on problem prevention, the techniques of continuous quality improvement represent a more effective means of maintaining high quality of data. This article describes the means by which principles of continuous quality improvement were incorporated into an HIV/AIDS clinical research network, as well as outcomes associated with these efforts. Han C, Pulling CC, Telke SE, Huppler Hullsiek K. Assessing the utility of five domains in SF-12 health status questionnaire in an AIDS clinical trial. AIDS 2002; 16:431-439.
Objective: To assess a shortened quality-of-life (QoL) measurement tool in a population with advanced HIV infection. Conclusions: For the domains considered, SF-12 is a reasonable and effective replacement for SF-39 in studies of patients with advanced HIV disease. SF-12 reduces item redundancy and the burden of data requirements for both investigators and patients; consequently, it may improve compliance with form completion. Tsai C, Chaloner K. Using prior opinions to examine sample size in a clinical trial: two
examples. Case Studies in Bayesian Statistics, Kass RE et al, eds. New York:
Springer-Verlag; 2001:409-423.
Chaloner K, Rhame FS. Quantifying and documenting prior beliefs in clinical trials.
Stat Med 2001; 20:581-600.
Collecting and documenting subjective prior beliefs from knowledgeable clinicians about the potential results of a clinical trial has many advantages. Two large trials or prophylactic treatments in an HIV-positive population are used as examples. The trials recruited patients of primary care physicians and compared treatments which were in use in clinical practice. Opinions about these trials were elicited from 58 practising HIV clinicians. It is shown how the documented opinions can be used by the monitoring board to anticipate the clinicians’ reaction to the results. Eliciting prior beliefs is also ethically important for documenting the nature of the uncertainty or equipoise. Important information is provided for the informed consent process and Institutional Review Board (IRB). Eberly LE, Ohman PA, Neaton, JD, Price RW, Abrams DI. Kaposi's Sarcoma and
central nervous system disease: a real association or an artifact of the control group?
AIDS 2000; 14:995-1000.
This was an observational study to test the hypothesis that Kaposi's sarcoma (KS) protects against four central nervous system (CNS) diseases in HIV-1-infected individuals. The study population of 9,404 subjects included participants from CPCRA protocols. The analyses indicate that the risk of CNS disease associated with Kaposi's sarcoma depends strongly on the reference or control group chosen. When compared to individuals with other non-KS AIDS-defining diseases, Kaposi's sarcoma is associated with a lower risk of CNS disease in HIV-1 positive individuals. However, when compared to individuals with no AIDS-defining disease or with a similarly mild AIDS-defining disease such as invasive candidiasis, Kaposi's sarcoma is associated with an equivalent risk of CNS disease. Johnson B, Carlin B, Hodges JS. Cross-study hierarchical modeling of stratified clinical
trial data. J Biopharm Stat1999;9(4):617-640.
Hierarchical random-effects models can be used to estimate treatment or other covariate effects in single-study analyses coordinated over multiple clinical units and can also be extended to a wide variety of cross-study applications. After reviewing the single-case study, we use data from five trial protocols to look for units that tend to have treatment effects consistently above or below the study-specific grand mean across several studies. As a first step, we summarize the patient-level data as study-specific and unit-specific estimated treatment effects and standard errors using independent Cox regression models. We then compare the results of a hierarchical model using these data summaries as input to those produced by a more fully Bayesian method that uses the actual patient-level survival data. We also compare various different models using a deviance information criterion, a recent extension of the Akaike information criterion designed for hierarchical models. Our procedure appears to be effective at answering the question whether certain clinical units of the Terry Beirn Community Programs for Clinical Research on AIDS are better than others at identifying treatment effects where they exist. Cox LE, Rouff JR, Svendsen KH, Markowitz M, Abrams DI. Community advisory boards: Their role in AIDS clinical trials. Health Soc Work 1998;23(4)290-297.
Community-based AIDS research programs were initially federally funded in 1989. Since then the Terry Beirn Community Programs for Clinical Research on AIDS has mandated that research units develop and maintain community advisory boards to provide advice and communicate community preferences in AIDS research. Seventeen community-based AIDS research units formed community advisory boards (CABs) based on a model developed by the Community Consortium at San Francisco General Hospital. Social workers employed by these AIDS research units surveyed 267 CAB members to ascertain board characteristics and members' perceptions of program activities. Implication for social work and future research are discussed. Green LA, Rhame FS, Price RW, Perlman DC, Capps LG, Sampson J, et al. Experience with a
cross-study endpoint review committee for AIDS clinical trials. AIDS 1998;12:1983-1990.
This paper describes the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted. Matts JP, Launer CA, Nelson ET, Miller C, Dain B. A graphical assessment of the potential
impact of losses to follow-up on the validity of study results. Stat Med 1997;16:1943-1954.
Losses to follow-up in clinical trials -- patients for whom it is unknown if the outcome of interest has occurred -- can bias study results. If we investigate extreme case scenarios and find the study results do not change much, impact is negligible. If not, we may need to interpret the study's results with caution. At issue is how much caution do we need? We describe a graphical approach to assess the potential impact of losses to follow-up on the validity of study results. One can create the graphs using design estimates and interim or final data. We give two examples using design parameters and another example modeled after observed data from clinical trials conducted by the CPCRA. The examples illustrate that tolerable levels of losses to follow-up change depending on the overall outcome and direction of differential losses. Larntz K, Neaton JD, Wentworth DN, Yurik T. Data analysis issues for protocols with
overlapping enrollment. Stat Med 1996;15:2445-2453.
Many persons with HIV require and take several medications. The efficacy and safety of many of these medications are uncertain. Approaches to data analysis, based on intention-to-treat, for individual and pairs of trials are described. An antiretroviral trial and a trial for prophylaxis of Pneumocystis carinii pneumonia (PCP) are used for illustration. The authors concluded that such analyses may yield useful information on drug interactions and that a more vigorous coenrollment policy should be pursued in AIDS research. Carlin BP. In: Gilks WR, Richardson S, Spiegelhalter DJ editors. Hierarchical longitudinal modeling. Markov Chain Monte Carlo in Practice. London: Chapman & Hall; 1996. p. 303-319.
Bayesian models of virtually unlimited complexity may now be seriously contemplated. Since most practicing statisticians learned the art of data analysis prior to the MCMC Baeysian revolution, most should probably receive a certain amount of retraining in order to avoid these pitfalls and take full advantage of this exciting new methodology. In the case of models for longitudinal data, several guidelines are given. Bjorling LE, Hodges JS. Rule-based ranking schemes for antiretroviral trials. Stat Med
1996;16:1175-1191
Often a trial's outcome measure is straightforward but not in trials of treatments for HIV infection. Currently, the nearly universal choice for a clinical outcome is the first occurrence or recurrence of an AIDS-defining condition or death. This paper discusses difficulties with this outcome measure and considers alternatives to it. This discussion leads to a consideration of rule-based ranking schemes that use more information than does first disease progression. Shih JH, Louis TA. Inferences on the association parameter in copula models for bivariate
survival data. Biometrics 1995;51:1384-1399.
A two-stage parametric and a two-stage semi-parametric estimation procedures for the association parameter in copula models are investigated. For the two-stage parametric estimation procedure, the estimate of the association parameter is efficient and the parameter estimates in the margins have high efficiency and are robust to misspecification of dependency structures. For the two-stage semi-parametric estimation, the estimate of the association parameter is efficient at independence. Proposed methods to an AIDS data set for illustration are applied. Neaton JD, Wentworth DN. Considerations in specifying the duration of followup of
antiretroviral trials. Med Biol Environ 1995;23(2):171-179.
This paper asserts that the duration of followup of antiretroviral trials should be longer and that research questions should be formulated as strategy questions with nested studies of specific agents of combination of agents. This approach has the potential for both quantifying the relative short term efficacy of specific drugs or combinations and providing data to develop better practice guidelines for using antiretrovirals over long time periods. Morse EV, Simon PM, Besch CL, Walker J. Issues of recruitment, retention, and compliance in
community-based clinical trials with traditionally underserved populations. Applied Nurs Res
1995; 8(1):8-14.
The investigators present data from a prospective study of potential barriers to enrollment and retention conducted during startup of 14 CPCRA units. The study had the additional purpose of delineating and evaluating the efficacy of various strategies used by the CPCRA clinical staff to reduce barriers to recruitment and retention. The study found that the success of the unit, in terms of its ability to accrue patients, may be dependent on its awareness of barriers and its ability to implement clinic-based strategies to enhance recruitment, retention, and compliance. Korzun A, Chaloner K. Protocol development. In: Finkelstein DM and Schoenfeld DA editors.
AIDS Clinical Trials. Wiley-Liss, Inc., New York; 1995. p. 67-89.
Besch CL. Compliance in clinical trials. AIDS 1995;9:1-10.
The author, in this editorial review, provides an overview of the types of compliance important positive and negative influencing factors, methods of measurement, and strategies that can improve compliance. The importance of compliance has been recognized in HIV research and care. Suggestions for future research with respect to HIV care include (1) identification of useful models of behavioral response that can predict or anticipate compliance with preventive and therapeutic treatments in the patient groups most impacted, (2) identification and description of cultural influences on medical care and response to health recommendations, and (3) development of specific interventions for the medically underserved populations affected by the HIV epidemic. Neaton JD, Wentworth DN, Rhame F, Hogan C, Abrams DI, Deyton L. Methods of studying
interventions: Considerations in choice of a clinical endpoint for AIDS clinical trials. Stat Med
1994;13:2107-2125.
In most clinical trials of antiretroviral therapy for patients infected with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS- defining event. The authors review features of combined endpoints and used data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty, and sensitivity. They conclude that the combined endpoint is not relevant because (1) the 19 different events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of death and (2) the events after the first are ignored, and, thus, the event profile of patients is not taken into account in making treatment comparisons. The authors recommend that survival be the primary endpoint of antiretroviral trials and that all opportunistic events experienced by patients, not just the first, be collected and summarized. Carlin BP, Chaloner KM, Louis TA, Rhame FS. Elicitation, monitoring, and analysis for an
AIDS clinical trial. Gatsonis C, Hodges JS, Kass RE, and Singpurwalla ND editors.
Case Studies in Bayesian Statistics. New York: Springer-Verlag; 1994 2:48-49.
Bayesian methods have been a subject of increasing interest among researchers engaged in the interim monitoring and final analysis of clinical trials data. In this paper the practical application of Bayesian methodology to the analysis of clinical trial data, with emphasis on issues particularly relevant for AIDS trials is discussed. The performance of this methodology when applied to a trial conducted by the CPCRA is reported. The results indicate which phases of the analysis are well handled using currently available techniques, and which phases seem to require further methodological development. Potential solutions to some of these problem areas and discussed and the nature of the research questions for some of those that remain are described. Chaloner K, Church T, Louis TA, Matts JP. Graphical elicitation of a prior distribution for a clinical trial. The Statistician 1993;42:341-353.
Bayesian methods are potentially useful for the design, monitoring and analysis of clinical trials. This paper describes a method to help quantify beliefs in the form of a prior distribution about regression coefficients in a proportional hazards regression model. The method was developed for, and is applied to, a randomized trial comparing prophylaxes for toxoplasmosis in a population of HIV-positive individuals. Prior distribution from five AIDS experts are elicited. Carlin BP, Chaloner K, Church T, Louis TA, Matts JP. Bayesian Approaches for monitoring
clinical trials with an application to toxoplasmic encephalitis prophylaxis. The Statistician
1993;42(4):355-367.
Bayesian methods have been a subject of increasing interest among researchers engaged in the interim monitoring and final analysis of clinical trials data. Computational issues are investigated by comparing the posterior distributions of model parameters obtained assuming approximate posterior normality with more precise results obtained via numerical integration. The impact of approximations on the performance of Bayesian stopping rules was also investigated. Where the normal approximation is inappropriate, the Bayesian methodology still allows for inference and simple monitoring displays based on posterior probabilities. The methodology with a numerical example featuring prior distributions elicited from five AIDS experts and data from a recently completed toxoplasmic encephalitis prophylaxis trials are illustrated. El-Sadr W, Capps L. The challenge of minority recruitment in clinical trials for AIDS. JAMA
1992;267(7):954-957.
There are significant obstacles to the participation of minorities in clinical trials. The problem of basing medical recommendations for the entire HIV-infected population on results of clinical trials in which minorities are not adequately represented is that the results may not apply to them and women. The authors suggests that the compelling scientific, ethical, and social reasons for inclusion of minorities in clinical trials justify the necessary efforts to accomplish this goal. The CPCRA program is an attempt to increase minority recruitment in HIV disease clinical trials. |