Biomedical subjects

C J Struchiner

Publications and source records attributed to C J Struchiner.

At least 37 records · Page 2Linked to original sources

PubMed1999

Limited-sampling strategy models for estimating the area under the plasma concentration-time curve for amlodipine.

OBJECTIVE: Develop and validate limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) of amlodipine, using data from a bioequivalence study. METHODS: Sixteen healthy volunteers received single 5-mg oral doses of amlodipine, as reference or test formulation, at a 14-day interval, in a randomized, crossover protocol. Plasma concentrations of amlodipine (n = 288), measured by mass spectrometry, were used to develop LSS models. RESULTS: Linear regression analysis of the AUC0-72 and a "jack-knife" validation procedure revealed that LSS models based on two sampling times (12 h and 48 h) predict accurately (R2 = 0.99; bias < 0.01%; precision = 0.03%) the AUC0-72 of amlodipine for each formulation. Validation tests indicate that the 2-point LSS model developed for the reference formulation predicts accurately (R2 > 0.90): (a) the individual AUC0-72 for the test formulation in the same group of volunteers; (b) the individual AUC0-72 for the same reference formulation in another bioequivalence study in Brazilian volunteers; (c) the average AUC0-72 reported in seven additional international studies performed under protocols similar to the present investigation; (d) the individual AUC0-72 corresponding to concentration data points provided by a first-order compartmental pharmacokinetic model, when the relative values of either the absorption rate (Kabs) or the bioavailability (F) model parameters were set at 0.85 or 0.6, of their respective original values. CONCLUSIONS: The 2-point LSS models developed in the current study predict accurately the AUC of amlodipine under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pharmacokinetics and pharmacodynamics of this calcium antagonist, at reduced costs of sample acquisition and analysis, and avoiding sampling at "unsociable" hours.

Administration, Oral↗

PubMed1999

Hepatitis A incidence rate estimates from a pilot seroprevalence survey in Rio de Janeiro, Brazil.

BACKGROUND: To assess the impact of water sanitation and sewage disposal, part of a major environmental control programme in Rio de Janeiro, we carried out sero-prevalence studies for Hepatitis A virus (HAV) in three micro-regions in Rio de Janeiro. Each region varied with regard to level of sanitation. We are interested in assessing the discriminating power of age-specific prevalence curves for HAV as a proxy for improvement in sanitation. These curves will serve as baseline information to future planned surveys as the sanitation programme progresses. METHODS: Incidence rate curves from prevalence data are estimated parametrically via a Weibull-like survival function, and non-parametrically via maximum likelihood and monotonic splines. Sera collected from children and adults in the three areas are used to detect antibodies against HAV through ELISA. RESULTS: We compare baseline incidence curves at the three sites estimated by the three methods. We observe a strong negative correlation between level of sanitation and incidence rates for HAV infection. Incidence estimates yielded by the parametric and non-parametric approaches tend to agree at early ages in the microregion showing the best level of sanitation and to increasingly disagree in the other two. CONCLUSION: Our results support the choice of HAV as a sentinel disease that is associated with level of sanitation. We also introduce monotonic splines as a novel non-parametric approach to estimate incidence from prevalence data. This approach outperforms current estimating procedures.

Adolescent↗

PubMed1999

Design and interpretation of vaccine field studies.

There are many different effects to consider when evaluating vaccines in the field. In this review, we have covered some of the various measures and issues related to study design and interpretation of the different measures. We emphasize that in designing and understanding vaccine studies, it is necessary to be specific about what the effect of interest is and about the assumptions underlying the interpretation of the results. Halloran et al. (81) present design, analysis, and interpretation of vaccine studies in more detail.

Disease Transmission, Infectious↗

PubMed1999

Limited-sampling strategy models for itraconazole and hydroxy-itraconazole based on data from a bioequivalence study.

The extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points (n = 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC0-infinity) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC0-infinity against time and a "jackknife" validation procedure revealed that models based on three sampling times accurately predict (R2, >0.98; bias, <3%; precision, 3 to 7%) the AUC0-infinity for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC0-infinity. The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC0-infinity reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC0-infinitys for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.

Adult↗

PubMed1998

Evaluation of SPf66 malaria vaccine efficacy in Brazil.

This paper reports the efficacy results of the randomized, placebo-controlled, field trial of SPf66 malaria vaccine in Costa Marques, Rondonia, Brazil. This region is characterized by the seasonal distribution of Plasmodium falciparum and P. vivax infections, and the recent occupation by migrants from nonendemic areas. A total of 800 individuals of both sexes, ranging in age from seven to 60 years, were included in the study. Of the initial cohort, 572 participants completed the vaccination schedule. Clinical and parasitologic evaluations were obtained by active and passive searches on a periodic basis. The overall protective efficacy against P. falciparum infections was -1.6% (-32.9% to 22.4%), and 14.1% (-17.0% to 36.9%) for the first episode. The overall protective efficacy for P. vivax infections was -19.7% (-44.8% to 1.03%), and -10.8% (-41.1% to 12.8%) for the first episode. No statistical evidence of an overall significant protective effect of SPf66 malaria vaccine against P. falciparum and P. vivax malaria was obtained in this trial.

Adolescent↗

PubMed1997

Study designs for evaluating different efficacy and effectiveness aspects of vaccines.

Vaccine efficacy and effectiveness (VE) are generally measured as 1 minus some measure of relative risk (RR) in the vaccinated group compared with the unvaccinated group (VE = 1 - RR). In designing a study to evaluate vaccination, the type of effect and the question of interest determine the appropriate choice of comparison population and parameter. Possible questions of interest include that of the biologic effect of vaccination on susceptibility, on infectiousness, or on progression to disease in individuals. The indirect effects, total effects, and overall public health benefits of widespread vaccination of individuals within the context of a vaccination program might also be of primary concern. The change in behavior induced by belief in the protective effects of vaccination might influence the estimates of these effects or might itself be of interest. In this paper, the authors present a framework of study designs that relates the scientific question of interest to the choice of comparison groups, the unit of observation, the level of information available for analysis, and the parameter of effect.

Algorithms↗

PubMed1996

Estimability and interpretation of vaccine efficacy using frailty mixing models.

The authors consider estimability and interpretation of vaccine efficacy based on time to event data, allowing that some of the population might have a very low probability of acquiring disease, and the rest have partial, possibly continuously distributed, susceptibility. The efficacy parameters of interest in the frailty mixing model include the fraction highly unlikely to acquire the infection or disease due to the vaccine, the degree of partial protection in those still susceptible, and the average protection or summary measure of efficacy under heterogeneity. The efficacy estimates can still be usefully interpreted when the heterogeneity results from heterogeneity in contact patterns, contact rates, or infectiousness of the contacts, as long as these are equal in the vaccinated and unvaccinated groups. A likelihood-based method allows estimation of the efficacy parameters of interest from grouped time to event data. Simulated vaccine studies assuming different levels and distributions of efficacy demonstrate that ignoring heterogeneity in susceptibility or exposure to infection generally results in underestimation of vaccine efficacy as well as incorrect interpretation of the estimates. The approach is also applicable to other covariates affecting susceptibility or exposure to infection in infectious diseases. Exploitation of the dependent happening structure of infectious diseases to obtain a shape for the baseline hazard may help identifiability. The authors recommend fitting several models to time to event data in vaccine studies.

Effect Modifier, Epidemiologic↗

PubMed1996

Rate estimation from prevalence information on a simple epidemiologic model for health interventions.

Health intervention control programs, such as vaccination, can be evaluated by comparing incidence rates of infection between unprotected and protected individuals in a population. The ratio of incidence rates is usually estimated by following up control and treated groups in order to collect information on person-time and cases in each group. This approach can be expensive and time consuming. An alternative approach is to use prevalence data to reconstitute incidence. Current-status are readily available or easily gathered and can be used to estimate incidence rates. Under certain assumptions of irreversibility for the outcome of interest, we discuss a simple transmission model appropriate to evaluate health interventions that confer long term protection. Rates and populations are parameter-free functions of age and calendar time. We develop general mathematical relationships that link incidence and intervention rates to prevalence which could be estimated from sampling without requiring knowledge of subpopulation demographics.

Communicable Disease Control↗

PubMed1995

Assessment of the direct effectiveness of BC meningococcal vaccine in Rio de Janeiro, Brazil: a case-control study.

BACKGROUND: Meningococcal disease is still a serious public health problem in many countries. A vaccine produced by Cuba was the first product against B meningococcus available on a large scale. In an attempt to control the increasing incidence of this serogroup in greater Rio de Janeiro, Brazil, the vaccine was used in 1990 in children aged 6 months-9 years. About 1.6 million children were vaccinated. METHODS: In order to assess the direct effectiveness of the vaccine in preventing disease, we conducted a case-control study during the first year after vaccination. Using a hospital-based census, we selected all children hospitalized with meningococcal disease and sampled the control group among children hospitalized with other types of meningitis. Vaccine effectiveness was estimated from the relationship, 1-OR, where OR (odds ratio) was the exponential of the logistic regression coefficient for the association between meningococcal disease and previous vaccination. RESULTS: A total of 275 cases and 279 controls were selected between September 1990 and October 1991. The summary adjusted measure of protection against serogroup B was 54% (95% confidence interval [CI]: 20-74%). Estimated protection varied among different age strata and place of residence, being high among children aged > or = 4 years, 71% (95% CI: 34-87%), and among those who lived in the City of Rio de Janeiro, 74% (95% CI: 42-89%). CONCLUSIONS: The results suggest that the vaccine produced by Cuba may offer protection against serogroup B meningococcal disease, but its effects may not be homogeneous.

Age Distribution↗

PubMed1995

Causal inference in infectious diseases.

Since the 1970s, Rubin has promoted a model for causal inference based on the potential outcomes if individuals received each of the treatments under study. Commonly, the assumption is made that the outcome in one individual is independent of the treatment assignment and outcome in other individuals. In infectious diseases, however, whether one person become infected is quite often dependent on the infection outcome in other individuals, a situation known as dependent happenings. Here, we review the model proposed by Rubin for the example of infectious disease. Consequences of the violation of the stability assumption include the need for an expanded representation of outcomes, and the existence of different kinds of effects, such as direct and indirect effects. Effects of interest include changes in susceptibility as well as changes in infectiousness. We define the transmission probability formally as an average causal parameter of effect in a population by conditioning on exposure to infection. Unconditional indirect and total effects are difficult to define formally using this model for causal inference. The assignment mechanism can influence the sampling mechanism when it determines who is exposed to infection, raising problems that require further inquiry. We conclude by contrasting the role of differential exposure to infection in direct and indirect effects.

Causality↗

PubMed1994

Exposure efficacy and change in contact rates in evaluating prophylactic HIV vaccines in the field.

Field studies of the efficacy of prophylactic vaccines in reducing susceptibility rely on the assumption of equal exposure to infection in the vaccinated and unvaccinated groups. Differential exposure to infection could, however, be the goal of other types of intervention programme, or it could occur secondary to belief in the protective effects of a prophylactic measure, such as vaccination. We call this differential exposure the exposure efficacy, or behaviour efficacy. To study the relative contribution of unequal exposure to infection and differential susceptibility to the estimate of vaccine efficacy, we formulate a simple model that explicitly includes both susceptibility and exposure to infection. We illustrate this on the example of randomized field trials of prophylactic human immunodeficiency virus vaccines. Increased exposure to infection in the vaccinated group may bias the estimated reduction in susceptibility. The bias in the estimate depends on the choice of efficacy parameter, the amount of information used in the analysis, the distribution and level of protection in the population, and the imbalance in exposure to infection. Sufficient increase in contacts in the vaccinated could result in the vaccine being interpreted as having an immunosuppressive effect. Estimates of vaccine efficacy are generally more robust to imbalances in exposure to infection when the detailed history of exposure to infection can be used in the analysis or at high levels of protection. The bias also depends on the relationship between the distribution of vaccine protection and the distribution of behaviour change, which could differ between blinded and unblinded trials.

AIDS Vaccines↗

PubMed1994

Epidemiologic effects of vaccines with complex direct effects in an age-structured population.

Vaccines can alter the dynamic interaction of an infectious agent with a host in complex ways. The effect of routine childhood immunization on age-specific cases was studied in an age-structured population, assuming different vaccine effects at the individual level. Assumptions about vaccine efficacy include partial protection to infection and disease, reduction in infectiousness, waning of protection, and boosting of the level and duration of protection by natural infection. The concept of relative pathogenicity is introduced to describe the effect of a vaccine on the development of disease conditional on being infected. The concepts of the immunologically naive susceptible, naive susceptible equivalent, and relative residual infection potential are introduced in the context of defining the reproduction number of a population vaccinated with a partially protective vaccine. Sensitivity to boosting has a particularly pronounced effect in reducing the number of older vaccinated cases. Near the threshold for eliminating transmission, the dynamic behavior and number as well as age distribution of cases is very sensitive to the degree of protection and relative residual infectiousness. The number of unvaccinated cases is more sensitive to the level of coverage than to the type of vaccine, while the number of vaccinated cases is very sensitive to assumptions about vaccine efficacy.

Adolescent↗

PubMed1993

On the distribution of vaccine protection under heterogeneous response.

We assume that individuals in a vaccinated cohort respond heterogeneously and acquire a continuous spectrum of effective protection against an environmental exposure to infection that can be varying in time. The notion of dynamical invariants is applied to a proportional hazard model with an unvaccinated or placebo cohort as baseline. The hazard is expressed as a susceptibility factor times a measure of environmental exposure to infection. Using the time-evolving information for the aggregated vaccinated cohort and the unvaccinated cohort, it is possible to reconstruct the distribution of effective protection imparted by the vaccination at the beginning of observation. Efficacy is defined in terms of the hazard ratio at the beginning of observation.

Communicable Disease Control↗

PubMed1992

Modeling transmission dynamics of stage-specific malaria vaccines.

Population effects of malaria vaccination programs will depend on a complex interaction of the stage specificity of the vaccine, its duration of effectiveness, whether it is responsive to natural boosting, the strategy implemented, the proportion vaccinated and the pre-existing endemic conditions. In this article, Elizabeth Halloran and Claudio Struchiner review models of malaria transmission that incorporate aspects of immunity relevant to studying the effects of stage-specific malaria vaccination programs. They discuss the difference in the assumptions and applicability of the models and compare their predictions. Experience with malaria has demonstrated the difficulty in eliminating transmission, so emphasis needs to be on the new host-parasite balance that will be induced by the vaccination program. Although Halloran and Struchiner advise caution in interpreting the results of such models, they conclude that quantitative and theoretical analysis will be important in planning and evaluating interventions with malaria vaccines.

Journal Article↗

PubMed1991

Direct and indirect effects in vaccine efficacy and effectiveness.

In 1915, Greenwood and Yule noted that for valid vaccine efficacy studies, exposure to infection in the vaccinated and the unvaccinated must be equal (Proc R Soc Med 1915;8(part 2):113-94). The direct effect of a vaccine, however, needs to be defined by the protection it confers given a specific amount of exposure to infection, not just a comparable exposure. In this paper, two classes of parameters are distinguished along lines differing from the conventional distinction between efficacy and effectiveness. Efficacy parameters attempt to control for exposure to infection and represent direct effects on individuals. Direct effectiveness parameters represent a mixture of direct effects on individuals and indirect effects in the population.

Environmental Exposure↗

PubMed1991

Study designs for dependent happenings.

In 1916, Sir Ronald Ross defined "dependent happenings" as events where the number affected in a unit of time depends on the number already affected. That is, the incidence depends on the prevalence, a characteristic of many infectious diseases. Because of this dependence, interventions against infectious diseases can have not only direct protective effects for the person receiving an intervention, but also indirect effects resulting from changes in the intensity of transmission in the population. This paper develops the conceptual framework for four types of study designs that differentiate and account for direct and indirect effects of intervention programs in dependent happenings.

Communicable Disease Control↗

PubMed1990

The behaviour of common measures of association used to assess a vaccination programme under complex disease transmission patterns--a computer simulation study of malaria vaccines.

Case-control studies have been evoked as important alternatives to randomized clinical trials in the evaluation of infectious disease interventions. Using computer simulations, we compare the behaviour of common measures of association derived from case-control studies in the context of a malaria vaccine programme administered under complex transmission conditions. Several simplifying assumptions of previous workers have been relaxed and the simulated conditions are endemic rather than epidemic. The common estimators of association used in case-control studies remain unbiased only in limited circumstances. The term dependent happenings, first defined by Ross in 1916, is resurrected. Since the number of people becoming infected is dependent on the number of people already infected, control programmes in infectious diseases produce direct as well as indirect effects. Three different study designs with different pairs of comparison populations are defined. The choice of comparison population can be used to differentiate direct from indirect effects. In order to clarify the direct effects of a vaccination programme the comparison groups must be subjected to identical transmission intensities. In contrast, the referent group must remain unaffected by consequences of the intervention to determine indirect effects.

Brazil↗

PubMed1989

Modeling malaria vaccines. I: New uses for old ideas.

Starting from a modification of the model of malaria transmission developed for the Garki project, this paper develops a model containing variables relevant to the stimulation of malaria vaccination programs. Modifications include (1) integration of maintenance of immunity dependent on boosting and the possibility of loss of immunity; (2) introduction of a boosting factor distinct from susceptibility to infection; (3) reinterpretation of the epidemiological compartments of positive immunes and nonimmunes in terms of severity of disease rather than just infection; (4) interpretation of the different stage-specific levels of immunity; (5) discrimination between different susceptibilities for the immune and nonimmune classes; (6) reformulation of the expression for acquisition of immunity to be biologically more acceptable. Simulations using the Garki model, Nedelman's modification of it, and our Basic model compare the similarities and differences in the predictive behavior of the models. Simulations using the Basic model reproduce observed periodic fluctuations of malaria attributed to the interplay of transmission-blocking immunity and loss of immunity in the absence of boosting in areas of unstable malaria transmission.

Animals↗