摘要:

AbstractBackcalculation has been used to estimate the rate of past HIV infection and to predict future AIDS incidence. In this study we examine another use: estimating the probability of progression from HIV infection to AIDS as a function of time from infection. Given observed AIDS incidence data, the technique of backcalculation estimates the most likely number of persons infected with HIV in the past. Assumptions about probability of progression from HIV infection to AIDS are necessary. By varying these assumptions and examining the resulting goodness of fit to the AIDS incidence data, we can theoretically estimate parameters of progression. We report on implementation of this method and examine its practical utility in deciding among four competing progression models specified ona priorigrounds. The four specific models comprise three Weibull distributions with medians of 8, 10, and 12 years, respectively, and one model that beings as a Weibull with 8 year median but where the hazard is level after 3.5 years. To employ asymptotic maximum likelihood methods, we define a two parameter family of progression models that includes all foura priorimodels. One parameter sets the scale for an initial Weibull progression (the shape parameter being fixed for all models), and the other specifies a levelling point after which the hazard remains constant.AIDS incidence data from Canada's national surveillance system provided the empiric data for this evaluation. First we corrected these data for reporting delay by Poisson modelling of the delay distribution. We used three parametric families of infection curves: step‐function, log‐logistic, and logistic.The results support the hypothesis of an early levelling of the hazard function. When we fixed the scale parameter to that of the Weibull curve with 8 year median, the maximum likelihood estimate of the levelling point was 2.7 years, and a clearly superior fit was produced compared to a pure Weibull progression with the same scale parameter (likelihood ratio chi‐square of 10.6 on 1 degree of freedom,p= 0.001). The maximum was indistinguishable in fit from the levelling point of 3.5 years hypothesized in advance (chi‐square = 0.30, d.f. = 1,p= 0.58). Backcalculation, however, could not determine the Weibull scale parameter itself because the likelihood was quite flat as a function of this parameter. We conclude that one must determine the parameters governing the initial shape of the hazard function from other kinds of data.We interpret the model with levelling of the hazard as an empirical description of progression in a real population rather than as natural history in a homogeneous population. We make comparisons with other recently proposed models of prog

ISSN:0277-6715    

DOI:10.1002/sim.4780120702

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractOrthogonal polynomial scores (OPS) is a simple, biologically meaningful approach to characterize longitudinal data in phase I and II clinical pharmacology trials. It describes average, linear, quadratic and higher order polynomial characteristics of each subject's response over time with use of composite scores computed from linear combinations of the observed data. The statistical evaluation of the composite scores is univariate. For studies with a small number of experimental units and with many repeated measures, OPS may offer advantages over the use of summary measures such as the maximum response (MAX), the time at which MAX occurred (TMAX), or the area under the response curve (AUC), and other popular approaches such as time‐point‐by‐time‐point, split‐plot, and multivariate

ISSN:0277-6715    

DOI:10.1002/sim.4780120703

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractTwo‐stage testing involves a preliminary test of a nuisance parameter prior to testing main hypothesis. In a two‐by‐two factorial trial, the treatment interaction is the nuisance to the inference about the efficacy of one of the treatments given alone. In comparing a combination therapy to both of its component therapies, the nuisance parameter is the difference in the component effects. When the preliminary test is an integral part of inference about the main parameter, the actual level of significance for the two‐stage test procedure can be much higher than the desired nominal level. If one places no restriction on the value of the nuisance parameter, then any two‐stage test with its significance level properly controlled has undesirable properties. This applies to comparative studies of combination agents relative to the component agents. When the interaction with an ineffective treatment is null, two‐stage testing may have some power advantage for assessing monothera

ISSN:0277-6715    

DOI:10.1002/sim.4780120704

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractMany bioassay procedures to test a new substance for toxicity, like some phase I clinical trials, can be modelled as first‐order Markov chains with absorbing states. We provide a general framework for such procedures. We show how one may calculate under any dose response curve assumption final absorption probabilities, and a number of total average costs such as time required until trial completion, number of subjects treated, number of subjects exhibiting unaceptable levels of toxicity, and amount of medication administered. One may use the above information associated with the trial for ana prioricomparison between competing designs under consideration. We provide an example of such a compariso

ISSN:0277-6715    

DOI:10.1002/sim.4780120705

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractTheP‐value after a repeated significance test is a useful measure of the strength of evidence against the null hypothesis. Its computation, however, requires a computer‐intensive numerical integration method. TheP‐value is not conceptually straightforward, because it depends on how the sample space is ordered, which can be arbitrary. We look at two orderings of the sample space, one proposed by Tsiatiset al.and the other by Rosner and Tsiatis, and Chang. Although studies have shown that the latter ordering gives more reasonable confidence intervals than the former, the former gives a conservative and therefore more reasonableP‐value. Both, however, should yield an identicalP‐value in most applications. In this paper we present a simple method of approximatingP‐values. We provide tables to implement the method for two to ten stages with α = 0.1, 0.05 and 0.01 for the Pocock and O'Brien‐Fleming procedures. The proposed method can be applied to

ISSN:0277-6715    

DOI:10.1002/sim.4780120706

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractConfidence limits for population prevalence based on the first occurrence of an item in a medical database, or for incidence based on time to first occurrence, should be based on the geometric or exponential distributions, respectively. These intervals are presented and compared with the corresponding intervals based on the binomial and Poisson distributions. The lower confidence limits are shown to be the same, but the upper limits are smaller, hence leading to shorter intervals. Applications of these intervals are also presented.

ISSN:0277-6715    

DOI:10.1002/sim.4780120707

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractIn a placebo‐controlled vaccine efficacy trial of a trial of equivalence of vaccines, one may wish to show that relative risk of disease is less than a specified valueR0, not equal to one. This paper compares three methods for estimating relative risk in the binomial setting, based on a logarithmic transformation, likelihood scores, and a Poisson approximation. Exact power and size of test are calculated by enumeration of possible binomial outcomes, and power is approximated from asymptotic formulations. Although the score method is generally preferable, for most studies of practical interest the log and score methods are comparable, and the Poisson method is also appropriate for small risks, up to about 0.05. When true and null relative risks are less than one, unequal allocation of study individuals can increase power, and the asymptotic formula for the log method may substantially understimate power; in such a study the power approximation for the score method is more reliable, even if the log method is used in analysis. Exact power calculations are helpful in planning studies. The log and Poisson methods, but not the score method, apply readily in the case of unequal follow

ISSN:0277-6715    

DOI:10.1002/sim.4780120708

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractTables of sample sizes for pair‐matched studies with binary outcome are presented. They are based on conditional and unconditional approaches using the ‘exact’ (binomial) test. An approximate procedure is suggested to estimate the sample size for parameter values that do not correspond exactly with table entries. The procedure utilizes a minor modification of the large‐sample formula given by Connettet al.A practical strategy for estimating the overall sample size in the presence of a nuisance parameter (the proportion of discordant pairs) is recommended. An example from a proposed clinical trial i

ISSN:0277-6715    

DOI:10.1002/sim.4780120709

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0277-6715    

DOI:10.1002/sim.4780120710

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0277-6715    

DOI:10.1002/sim.4780120711

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY