Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-analysis of the Published Literature
TL;DR: Protection against tuberculous death, meningitis, and disseminated disease is higher than for total TB cases, although this result may reflect reduced error in disease classification rather than greater BCG efficacy.
Abstract: Objective. —To quantify the efficacy of BCG vaccine against tuberculosis (TB). Data Sources. —MEDLINE with index termsBCG vaccine, tuberculosis, andhuman. Experts from the Centers for Disease Control and Prevention and the World Health Organization, among others, provided lists of all known studies. Study Selection. —A total of 1264 articles or abstracts were reviewed for details on BCG vaccination, concurrent vaccinated and unvaccinated groups, and TB outcome; 70 articles were reviewed in depth for method of vaccine allocation used to create comparable groups, equal surveillance and follow-up for recipient and concurrent control groups, and outcome measures of TB cases and/or deaths. Fourteen prospective trials and 12 case-control studies were included in the analysis. Data Extraction. —We recorded study design, age range of study population, number of patients enrolled, efficacy of vaccine, and items to assess the potential for bias in study design and diagnosis. At least two readers independently extracted data and evaluated validity. Data Synthesis. —The relative risk (RR) or odds ratio (OR) of TB provided the measure of vaccine efficacy that we analyzed. The protective effect was then computed by 1 —RR or 1 —OR. A random-effects model estimated a weighted average RR or OR from those provided by the trials or case-control studies. In the trials, the RR of TB was 0.49 (95% confidence interval [Cl], 0.34 to 0.70) for vaccine recipients compared with nonrecipients (protective effect of 51%). In the case-control studies, the OR for TB was 0.50 (95% CI, 0.39 to 0.64), or a 50% protective effect. Seven trials reporting tuberculous deaths showed a protective effect from BCG vaccine of 71% (RR, 0.29; 95% Cl, 0.16 to 0.53), and five studies reporting on meningitis showed a protective effect from BCG vaccine of 64% (OR, 0.36; 95% Cl, 0.18 to 0.70). Geographic latitude of the study site and study validity score explained 66% of the heterogeneity among trials in a random-effects regression model. Conclusion. —On average, BCG vaccine significantly reduces the risk of TB by 50%. Protection is observed across many populations, study designs, and forms of TB. Age at vaccination did not enhance predictiveness of BCG efficacy. Protection against tuberculous death, meningitis, and disseminated disease is higher than for total TB cases, although this result may reflect reduced error in disease classification rather than greater BCG efficacy. (JAMA. 1994;271:698-702)
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TL;DR: The metafor package provides functions for conducting meta-analyses in R and includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models.
Abstract: The metafor package provides functions for conducting meta-analyses in R. The package includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models. Meta-regression analyses with continuous and categorical moderators can be conducted in this way. Functions for the Mantel-Haenszel and Peto's one-step method for meta-analyses of 2 x 2 table data are also available. Finally, the package provides various plot functions (for example, for forest, funnel, and radial plots) and functions for assessing the model fit, for obtaining case diagnostics, and for tests of publication bias.
11,237 citations
TL;DR: The results of well-designed observational studies (with either a cohort or a case-control design) do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.
Abstract: Background In the hierarchy of research designs, the results of randomized, controlled trials are considered to be evidence of the highest grade, whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects. We used published meta-analyses to identify randomized clinical trials and observational studies that examined the same clinical topics. We then compared the results of the original reports according to the type of research design. Methods A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of randomized, controlled trials and meta-analyses of either cohort or case–control studies that assessed the same intervention. For each of five topics, summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual randomized, controlled trials and the individual observational studies. Results For the five clinical topics and 99 r...
3,259 citations
TL;DR: This tutorial on advanced statistical methods for meta-analysis can be seen as a sequel to the recent Tutorial in Biostatistics on meta- analysis by Normand, which focused on elementary methods.
Abstract: This tutorial on advanced statistical methods for meta-analysis can be seen as a sequel to the recent Tutorial in Biostatistics on meta-analysis by Normand, which focused on elementary methods. Within the framework of the general linear mixed model using approximate likelihood, we discuss methods to analyse univariate as well as bivariate treatment effects in meta-analyses as well as meta-regression methods. Several extensions of the models are discussed, like exact likelihood, non-normal mixtures and multiple endpoints. We end with a discussion about the use of Bayesian methods in meta-analysis. All methods are illustrated by a meta-analysis concerning the efficacy of BCG vaccine against tuberculosis. All analyses that use approximate likelihood can be carried out by standard software. We demonstrate how the models can be fitted using SAS Proc Mixed.
1,417 citations
TL;DR: It is proposed that vaccination induces IL-17-producing CD4+ T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4- T cells producing interferon-γ, which ultimately restrict bacterial growth.
Abstract: IL-23 and IL-17 in the establishment of protective pulmonary CD4 + T cell responses after vaccination and during Mycobacterium tuberculosis challenge
1,343 citations
TL;DR: Standard diagnostic procedures developed for linear regression analyses are extended to the meta-analytic fixed- and random/mixed-effects models to illustrate the usefulness of these procedures in various research settings.
Abstract: The presence of outliers and influential cases may affect the validity and robustness of the conclusions from a meta-analysis. While researchers generally agree that it is necessary to examine outlier and influential case diagnostics when conducting a meta-analysis, limited studies have addressed how to obtain such diagnostic measures in the context of a meta-analysis. The present paper extends standard diagnostic procedures developed for linear regression analyses to the meta-analytic fixed- and random/mixed-effects models. Three examples are used to illustrate the usefulness of these procedures in various research settings. Issues related to these diagnostic procedures in meta-analysis are also discussed. Copyright © 2010 John Wiley & Sons, Ltd.
1,335 citations
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TL;DR: This paper examines eight published reviews each reporting results from several related trials in order to evaluate the efficacy of a certain treatment for a specified medical condition and suggests a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.
33,234 citations
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15 Jan 1987
TL;DR: The core of the subject remains essentially simple, and a good epidemiological study should be capable of describing in such a way that all who are interested in the cause of disease can follow the argument and decide for themselves the validity of the conclusions as mentioned in this paper.
Abstract: Epidemiology is the simplest and most direct method of studying the causes of disease in humans, and many major contributions have been made by studies that have demanded nothing more than the ability to count, to think logically, and to have an imaginative idea. With the accumulation of knowledge, however, its has become harder for individuals working alone to make effective contributions, and epidemiological research is becoming increasingly a matter of teamwork, not only because of the large number of people that may have to be studied and the large amount of data that have to be collected and analyzed, but also because of the need to bring together for the design and conduct of the study clinical experience, biological understanding, statistical expertise, and many other special skills that vary from one study to another. But if, in this sense, epidemiological research is becoming more complex, the core of the subject remains essentially simple, and a good epidemiological study should be capable of description in such a way that all who are interested in the cause of disease can follow the argument and decide for themselves the validity of the conclusions.
2,797 citations
TL;DR: In this paper, a review of the state of the art in multiparameter shrinkage estimators with emphasis on the empirical Bayes viewpoint, particularly in the case of parametric prior distributions, is presented.
Abstract: This article reviews the state of multiparameter shrinkage estimators with emphasis on the empirical Bayes viewpoint, particularly in the case of parametric prior distributions. Some successful applications of major importance are considered. Recent results concerning estimates of error and confidence intervals are described and illustrated with data.
1,409 citations
TL;DR: It is concluded that an urgent need exists for improved methods in literature searching, quality evaluation of trials, and synthesizing of the results.
Abstract: A new type of research, termed meta-analysis, attempts to analyze and combine the results of previous reports. We found 86 meta-analyses of reports of randomized controlled trials in the English-language literature. We evaluated the quality of these meta-analyses, using a scoring method that considered 23 items in six major areas--study design, combinability, control of bias, statistical analysis, sensitivity analysis, and application of results. Only 24 meta-analyses (28 percent) addressed all six areas, 31 (36 percent) addressed five, 25 (29 percent) addressed four, 5 (6 percent) addressed three, and 1 (1 percent) addressed two. Of the 23 individual items, between 1 and 14 were addressed satisfactorily (mean +/- SD, 7.7 +/- 2.7). We conclude that an urgent need exists for improved methods in literature searching, quality evaluation of trials, and synthesizing of the results.
1,213 citations
TL;DR: Important design and statistical issues of this process of combining study results that can be used to draw conclusions about therapeutic effectiveness or to plan new studies are reviewed.
Abstract: Meta-analysis is the process of combining study results that can be used to draw conclusions about therapeutic effectiveness or to plan new studies. We review important design and statistical issues of this process. The design issues include protocol development, objectives, literature search, publication bias, measures of study outcomes, and quality of the data. The statistical issues include consistency (homogeneity) of study outcomes, and techniques for pooling results from several studies. Guidelines are provided to assess the quality of meta-analyses based on our discussion of the design and statistical issues. Limitations and areas for further development of this approach are discussed; researchers should come to a general agreement on how to conduct meta-analysis. As an explicit strategy for summarizing results, meta-analysis may help clinicians and researchers better understand the findings of clinical studies.
1,137 citations