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Biomedical subjects

M E Halloran

Publications and source records attributed to M E Halloran.

At least 37 records · Page 2Linked to original sources

Predictors of Chlamydia trachomatis infection among female adolescents: a longitudinal analysis.

Screening guidelines recommend testing all sexually active female adolescents for Chlamydia trachomatis during a pelvic examination at each clinic visit. Such criteria have been based on cross-sectional studies; new evaluations should take into account multiple clinic visits and assess whether criteria are appropriate when a prior test is negative and risk factors are absent. Because repeated observations on an individual may be correlated, the authors used the generalized estimating equation method. Little information exists on subsequent risk of infection; as control programs develop, approaches targeting high-risk populations for recurrent infections are needed. Using data on females aged 15-19 years who visited family planning clinics more than once from 1988 to 1992 (n = 26,921) in Region X (Alaska, Idaho, Oregon, and Washington), the authors constructed a retrospective cohort. Teens with chlamydia at their first visit were at high risk for subsequent infection (odds ratio = 1.6, 95% confidence interval 1.4-1.7). Among teens uninfected at the first visit and without risk factors at the second, prevalence at the second visit was 6%. When intervisit correlations using the generalized estimating equation method were taken into account, predictors of chlamydial infection were consistent with those in previous cross sectional studies cervicitis, friable cervix, and multiple, new, or symptomatic sex partner(s). These findings support screening sexually active female adolescents at each visit, even if prior tests results are available.

Adolescent↗

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↗

Recent developments in theories of pathogenesis of AIDS.

Experimental and theoretical progress in HIV research includes an improved resolution of the spatial heterogeneity and the dynamics (time course and turnover rates) of virus and CD4+ cells. Some of these advances have resulted from the joint work of experimental and theoretical groups, demonstrating that interdisciplinary research can be fruitful.

Acquired Immunodeficiency Syndrome↗

Epidemiologic effects of varicella vaccination.

For a plausible range of values for the different efficacy characteristics of the live varicella (Oka) vaccine at different levels of coverage, modeling results suggest that routine immunization of preschool children would greatly reduce the number of primary varicella cases, whereas the shift in age distribution of cases would not result in increased overall morbidity as measured by number of hospitalizations. Although information about some of the vaccine assumptions is scanty, the combinations of assumptions leading to an increase in morbidity seem unlikely. A catch-up program in older children who have not yet had chickenpox will be important. The number and age distribution of the cases in vaccinees are sensitive to assumptions about the vaccine, especially the degree and distribution of partial protection against infection, relative residual infectiousness, and waning of immunity. Responsiveness to boosting by wild-type VZV infection was especially important in reducing the number of older cases. The advantage conferred by responsiveness to boosting depends on the level of transmission. The direct and indirect effects of vaccines and vaccination programs interact. Understanding how a vaccine works at the individual level is important for the vaccinated individual, but it also influences the overall public health benefits of an immunization programs. Lieu et al based a cost-effectiveness analysis of varicella vaccines on this model of varicella dynamics and assumptions about how the vaccines work. Models cannot replace biologic understanding. The purpose of such models is not to predict the number of cases of varicella, but to examine some possible consequences of introducing a vaccine into the routine immunization schedule of preschool children in the United States, effects of different vaccination strategies, and the benefits of a temporary catch-up program for older children. Modeling exercises of this sort force us to formalize our thinking, for instance about the vaccine mechanisms, and to admit our uncertainties, such as about the vaccine efficacy assumptions. Such models also show where more data need to be collected, for example, on boosting and waning of immunity and relative residual infectiousness. Improvements in the design of vaccine efficacy studies are necessary to provide the input to these models for looking at the long-term effects of vaccination programs. Frailty models can be used to analyze the data in the presence of heterogeneities in susceptibility. Waning can also be estimated using appropriate methods. Relative infectiousness of vaccinees with breakthrough cases can be measured by comparing the relative secondary attack rates when the index infected person is vaccinated and when the index infected person is unvaccinated. More studies are needed to understand how to evaluate responsiveness to boosting. Vaccine efficacy studies in the field should be designed to obtain better estimates of residual susceptibility, residual infectiousness, duration of protection, and the effects of boosting by reinfection with wild-type VZV.

Adolescent↗

The effect of disease prior to an outbreak on estimates of vaccine efficacy following the outbreak.

A common source of bias in evaluating vaccine efficacy following a disease outbreak is the presence of persons who had the disease prior to the outbreak. This paper examines the effects of including and excluding pre-outbreak disease cases from the calculation of vaccine efficacy based on the cumulative incidence at the end of an outbreak. Using a five-stage model, the effects of the following factors on the bias of vaccine efficacy estimates are examined: the true protective efficacy of the vaccine, the prevaccination infection rate, differences in vaccine uptake among the previously diseased and nondiseased, differences in pre-outbreak exposure to infection between vaccinees and nonvaccinees, and differences in exposure during the outbreak between vaccinees and nonvaccinees. Numerical calculations of the bias are performed for a hypothetical outbreak of measles in a developing country. Exclusion of pre-outbreak disease cases requires accurate data on disease rates prior to the outbreak, and such data are often unreliable or nonexistent. Inclusion of pre-outbreak cases contributes to the bias of the estimated vaccine efficacy, especially when there is a high prevaccination infection rate and vaccine uptake among the previously diseased is considerably lower than that among the nondiseased. In most practical cases, however, this bias is not very large.

Disease Outbreaks↗

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↗

On individual and population effectiveness of vaccination.

BACKGROUND: The protective effect of a vaccine following an outbreak is often measured by the vaccine efficacy statistic, namely one minus the ratio of attack rates in vaccinees and non-vaccinees. This quantity is not an adequate measure of the population-level benefits of the vaccine. METHODS: We discuss two measures of the effectiveness of a vaccination programme. The first is the commonly used vaccine efficacy statistic. This is called here the individual vaccination effectiveness. The second measure, called the population effectiveness, is defined as one minus the ratio of the overall (or average) attack rate in the population when the vaccination programme is implemented to the expected attack rate in the same population without vaccination. We outline a method for computing the population effectiveness following an outbreak of a directly transmitted acute infectious disease in a closed heterogeneous population. We then explore and compare the behaviour of the two measures of vaccination effectiveness under various conditions. RESULTS: The population vaccination effectiveness is more robust than individual effectiveness to factors that may interfere with the evaluation of the performance of vaccination. Such factors are non-uniform vaccination, changes in contact patterns by vaccinees, and the ability of the vaccine to reduce infectiousness. CONCLUSION: The population vaccination effectiveness is a more adequate measure of the population-level benefits of a vaccination programme. The main disadvantage of this measure is that it cannot be readily calculated from observed attack rates.

Immunization Programs↗

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↗

Theoretical epidemiologic and morbidity effects of routine varicella immunization of preschool children in the United States.

The authors studied the effects of routine varicella immunization of US preschool children and of implementation of a catch-up program in older children on the age distribution of cases and on overall morbidity, with emphasis on the sensitivity of the results to level of vaccine coverage, duration of protection, responsiveness to boosting, relative residual susceptibility and infectiousness, and degree of morbidity among vaccine breakthrough cases. An age-structured theoretical transmission model was used, with values for vaccine efficacy based on a review of the literature by an expert panel. Although implementation of a vaccination program resulted in a shift in the age distribution of remaining varicella cases toward older ages with higher complication rates, the overall reduction in cases resulted in decreased morbidity as measured by overall number of hospitalizations and number of primary cases. Routine immunization with live-virus varicella vaccine would probably result in a substantial reduction in the number of uncomplicated primary cases of chickenpox, as well as a decreased number of complicated cases requiring hospitalization. The number and age distribution of vaccinated cases would depend strongly on the characteristics of the vaccine. Vaccine efficacy studies in the field should be designed to obtain better estimates of residual susceptibility, residual infectiousness, duration of protection, and effects of boosting by wild-type reinfection.

Age Distribution↗

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↗

Cost-effectiveness of a routine varicella vaccination program for US children.

OBJECTIVE: To evaluate the economic consequences of a routine varicella vaccination program that targets healthy children. METHODS: Decision analysis was used to compare the costs, outcomes, and cost-effectiveness of a routine vaccination program with no intervention. Clinical outcomes were based on a mathematical model of vaccine efficacy that relied on published and unpublished data and on expert opinion. Medical utilization rates and costs were collected from multiple sources, including the Kaiser Permanente Medical Care Program and the California Hospital Discharge Database. RESULTS: A routine varicella vaccination program for healthy children would prevent 94% of all potential cases of chickenpox, provided the vaccination coverage rate is 97% at school entry. It would cost approximately $162 million annually if one dose of vaccine per child were recommended at a cost of $35 per dose. From the societal perspective, which includes work-loss costs as well as medical costs, the program would save more than $5 for every dollar invested in vaccination. However, from the health care payer's perspective (medical costs only), the program would cost approximately $2 per chickenpox case prevented, or $2500 per life-year saved. The medical cost of disease prevention was sensitive to the vaccination coverage rate and vaccine price but was relatively insensitive to assumptions about vaccine efficacy within plausible ranges. An additional program for catch-up vaccination of 12-year-olds would have high incremental costs if the vaccination coverage rate of children of preschool age were 97%, but would result in net savings at a coverage rate of 50%. CONCLUSIONS: A routine varicella vaccination program for healthy children would result in net savings from the societal perspective, which includes work-loss costs as well as medical costs. Compared with other prevention programs, it would also be relatively cost-effective from the health care payer's perspective.

Acyclovir↗

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↗

Empirical Bayes methods for stabilizing incidence rates before mapping.

The epidemiologic utility of mapping and ranking incidence rates is often questioned owing to instability of the observed incidence values in areas with small populations. Spurious fluctuations in the observed rates caused by this instability can mask true spatial and temporal trends in risk. To produce maps with the required level of geographic resolution, yet based on reliable estimates, it is desirable to reduce the random variation in the observed rates before mapping. In this paper, we describe the empirical Bayes approach for obtaining stabilized incidence estimates. We begin by deriving Bayes rate estimators and then illustrate how using the observed rates to estimate unknown distributional information leads to the empirical Bayes formulation. A drawback of the approach is that the histogram of the empirical Bayes rate estimates may be narrower than the true distribution of risk. We outline a constrained empirical Bayes approach that produces improved estimators for the true distribution of the unknown rates. We include discussions of relevant previous applications of empirical Bayes methods to rate mapping problems and an evaluation of the strengths and weaknesses of the approach.

Bayes Theorem↗

Measuring vaccine efficacy from epidemics of acute infectious agents.

A good measure of field vaccine efficacy should evaluate the direct protective effect of vaccination on the person who receives the vaccine. The conventional estimator for vaccine efficacy depends on population level factors that are either unrelated or indirectly related to the direct biological action of the vaccine on persons, including population structure, duration of the study, the fraction vaccinated, and herd immunity, that is, indirect effects. Indirect effects can cause the conventional vaccine efficacy estimator to be inaccurate. We review alternative vaccine efficacy estimators that control for indirect effects at the population level. Thus, they are more accurate than the conventional estimator. We use epidemic simulations to explore the robustness of the conventional and proposed estimators under different field conditions. In addition, we apply the different vaccine efficacy estimators to data from a measles epidemic in Muyinga, Burundi.

Burundi↗

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↗

Malaria: living with drug resistance.

The epidemiological factors associated with the development and spread of drug-resistant malaria have been recently explored by Wemsdorfer in a paper in which he looked at parasite-drug-human-vector interactions that affect the occurrence and dynamics of drug resistance. The question that decision-makers must be asking themselves, as we face the 21st century, is: how will we live with drug resistance? Allan Schapira, Peter Beales and M. Elizabeth Halloran are ideally placed to consider this question. Extracting lessons from the past, they focus on drug-resistant Plasmodium falciparum in Africa. They propose a mathematical model, which will improve the conceptual basis for policy decisions and which has implications for drug development as well as for malaria-control programmes.

Journal Article↗