Ideally, a meta-analysis will summarize data from several unbiased studies. Here we consider the less than ideal situation in which contributing studies may be compromised by measurement error. Measurement error affects every study design, from randomized controlled trials to retrospective observational studies. We outline a flexible Bayesian framework for continuous outcome data which allows one to obtain appropriate point and interval estimates with varying degrees of prior knowledge about the magnitude of the measurement error. We also demonstrate how, if individual-participant data (IPD) are available, the Bayesian meta-analysis model can adjust for multiple participant-level covariates, measured with or without measurement error.
Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior pr…
Bivariate meta-analysis provides a useful framework for combining information across related studies and has been utilised to combine evidence from clinical studies to evaluate treatment efficacy on two outcomes. It has also been used to investigate surrogacy patterns between treatment effects on the surrogate endpoint and the final outcome. Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final outcome and to predict clinical benefit or harm. The standard bivariate meta-analytic approach models the observed …
Multivariate meta-analysis (MMA) is a powerful tool for jointly estimating multiple outcomes' treatment effects. However, the validity of results from MMA is potentially compromised by outcome reporting bias (ORB), or the tendency for studies to selectively report outcomes. Until recently, ORB has been understudied. Since ORB can lead to biased conclusions, it is crucial to correct the estimates of effect sizes and quantify their uncertainty in the presence of ORB. With this goal, we develop a Bayesian selection model to adjust for ORB in MMA. We further propose a measure for quantifying the i…
A common problem in the analysis of multiple data sources, including individual participant data meta-analysis (IPD-MA), is the misclassification of binary variables. Misclassification may lead to biased estimates of model parameters, even when the misclassification is entirely random. We aimed to develop statistical methods that facilitate unbiased estimation of adjusted and unadjusted exposure-outcome associations and between-study heterogeneity in IPD-MA, where the extent and nature of exposure misclassification may vary across studies. We present Bayesian methods that allow misclassificati…
Dose-response models express the effect of different dose or exposure levels on a specific outcome. In meta-analysis, where aggregated-level data is available, dose-response evidence is synthesized using either one-stage or two-stage models in a frequentist setting. We propose a hierarchical dose-response model implemented in a Bayesian framework. We present the model with cubic dose-response shapes for a dichotomous outcome and take into account heterogeneity due to variability in the dose-response shape. We develop our Bayesian model assuming normal or binomial likelihood and accounting for …
Step-by-Step Guide to Conducting Meta-Analysis of Dichotomous Outcomes Using RevMan in Dental Research Step-by-Step Guide to Conducting Meta-Analysis of Dichotomous Outcomes Using RevMan in Dental Research
Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final clinical outcome and to predict clinical benefit or harm. Such endpoints are assessed for their predictive value of clinical benefit by investigating the surrogate relationship between treatment effects on the surrogate and final outcomes using meta-analytic methods. When surrogate relationships vary across treatment classes, such validation may fail due to limited data within each treatment class. In this paper, two alternative Bayesian meta-analytic met…
Observational studies are needed when experiments are not possible. Within study comparisons (WSC) compare observational and experimental estimates that test the same hypothesis using the same treatment group, outcome, and estimand. Meta-analyzing 39 of them, we compare mean bias and its variance for the eight observational designs that result from combining whether there is a pretest measure of the outcome or not, whether the comparison group is local to the treatment group or not, and whether there is a relatively rich set of other covariates or not. Of these eight designs, one combines all …
Adjusting for Outcome Reporting Bias in Meta-analysis: A Multiple Imputation Approach
Epidemiology, Biostatistics and Prevention Institute (EBPI)（流行病学、生物统计学与预防研究所）；Center for Reproducible Science and Research Synthesis (CRS)（可重复科学与研究综合中心）；University of Zurich (UZH)（苏黎世大学）
Random-effects meta-analyses are very commonly used in medical statistics. Recent methodological developments include multivariate (multiple outcomes) and network (multiple treatments) meta-analysis. Here we provide a new model and corresponding estimation procedure for multivariate network meta-analysis, so that multiple outcomes and treatments can be included in a single analysis. Our new multivariate model is a direct extension of a univariate model for network meta-analysis that has recently been proposed. We allow two types of unknown variance parameters in our model, which represent betw…
Testing effect size homogeneity is an essential part when conducting a meta-analysis. Comparative studies of effect size homogeneity tests in case of binary outcomes are found in the literature, but no test has come out as an absolute winner. A alternative approach would be to carry out multiple effect size homogeneity tests on the same meta-analysis and combine the resulting dependent p-values. In this article we applied the correlated Lancaster method for dependent statistical tests. To investigate the proposed approach's performance, we applied eight different effect size homogeneity tests …
Three electronic searches were conducted to obtain articles in English limited to clinical human studies published prior to March 2015. The outcome measure was the success of MIs. Patient factors included age, gender, and jaw; the MI factors included length and diameter. A metaanalysis was then performed based on 17 individual studies. The quality of each study was assessed for nonrandomized studies and quantified using the NewcastleOttawa Scale. The outcome of the metaanalysis was a combined OR. Subgroup and sensitivity analyses based on the study design, study quality, and sample size of MI …
Publication bias occurs when the publication of research results depends not only on the quality of the research but also on its nature and direction. The consequence is that published studies may not be truly representative of all valid studies undertaken, and this bias may threaten the validity of systematic reviews and meta-analyses - on which evidence-based medicine increasingly relies. Multivariate meta-analysis has recently received increasing attention for its ability reducing potential bias and improving statistical efficiency by borrowing information across outcomes. However, detectin…
Comparative binary outcome data are of fundamental interest in statistics and are often pooled in meta-analyses. Here we examine the simplest case where for each study there are two patient groups and a binary event of interest, giving rise to a series of $2 \times 2$ tables. A variety of measures of treatment effect are then available and are conventionally used in meta-analyses, such as the odds ratio, the risk ratio and the risk difference. Here we propose a new type of measure of treatment effect for this type of data that is very easily interpretable by lay audiences. We give the rational…
The prediction of cancer prognosis and metastatic potential immediately after the initial diagnoses is a major challenge in current clinical research. The relevance of such a signature is clear, as it will free many patients from the agony and toxic side-effects associated with the adjuvant chemotherapy automatically and sometimes carelessly subscribed to them. Motivated by this issue, Ein-Dor (2006) and Zuk (2007) presented a Bayesian model which leads to the following conclusion: Thousands of samples are needed to generate a robust gene list for predicting outcome. This conclusion is based o…
An Online Meta-Level Adaptive Design Framework with Targeted Learning Inference: Applications to Evaluating and Utilizing Surrogate Outcomes in Adaptive Designs
Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta-analyses. The most well-known reasons for small study effects include publication bias, outcome reporting bias and clinical heterogeneity. Methods to account for small study effects in univariate meta-analysis have been extensively studied. However, detecting small study effects in a multivariate meta-analysis setting remains an untouched research area. One of the complications is that different types of selection process…
Researchers increasingly use meta-analysis to synthesize the results of several studies in order to estimate a common effect. When the outcome variable is continuous, standard meta-analytic approaches assume that the primary studies report the sample mean and standard deviation of the outcome. However, when the outcome is skewed, authors sometimes summarize the data by reporting the sample median and one or both of (i) the minimum and maximum values and (ii) the first and third quartiles, but do not report the mean or standard deviation. To include these studies in meta-analysis, several metho…
Identifying compromise solutions across multiple treatment benefit-harm profiles in multivariate network meta-analysis
Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center-University of Freiburg（弗赖堡大学医学院医学生物计量与统计研究所）；Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo（奥斯陆大学生物统计系奥斯陆生物统计与流行病学中心）
Although the lymphatic system is clearly linked to the metastasis of most human carcinomas, the mechanisms by which lymphangiogenesis occurs in response to the presence of carcinoma remain unclear. Hierarchical models are presented to investigate the properties of lymphatic vessel production in 2997 fields taken from 20 individuals with invasive carcinoma, 21 individuals with cervical intraepithelial neoplasia and 21 controls. Such data demonstrate a high degree of correlation within tumour samples from the same individual. Joint hierarchical models utilising shared random effects are discusse…
An absolute measure of heterogeneity for lnOR in meta-analysis
Beijing University of Technology（北京工业大学）；Yunnan University of Finance and Economics（云南财经大学）；Renmin University of China（中国人民大学）；Hong Kong Baptist University（香港浸会大学）
We consider the problem of meta-analyzing two-group studies that report the median of the outcome. Often, these studies are excluded from meta-analysis because there are no well-established statistical methods to pool the difference of medians. To include these studies in meta-analysis, several authors have recently proposed methods to estimate the sample mean and standard deviation from the median, sample size, and several commonly reported measures of spread. Researchers frequently apply these methods to estimate the difference of means and its variance for each primary study and pool the di…
We consider the setting of an aggregate data meta-analysis of a continuous outcome of interest. When the distribution of the outcome is skewed, it is often the case that some primary studies report the sample mean and standard deviation of the outcome and other studies report the sample median along with the first and third quartiles and/or minimum and maximum values. To perform meta-analysis in this context, a number of approaches have recently been developed to impute the sample mean and standard deviation from studies reporting medians. Then, standard meta-analytic approaches with inverse-v…
Many clinical endpoint measures, such as the number of standard drinks consumed per week or the number of days that patients stayed in the hospital, are count data with excessive zeros. However, the zero-inflated nature of such outcomes is sometimes ignored in analyses of clinical trials. This leads to biased estimates of study-level intervention effect and, consequently, a biased estimate of the overall intervention effect in a meta-analysis. The current study proposes a novel statistical approach, the Zero-inflation Bias Correction (ZIBC) method, that can account for the bias introduced when…
An aggregate data meta-analysis is a statistical method that pools the summary statistics of several selected studies to estimate the outcome of interest. When considering a continuous outcome, typically each study must report the same measure of the outcome variable and its spread (e.g., the sample mean and its standard error). However, some studies may instead report the median along with various measures of spread. Recently, the task of incorporating medians in meta-analysis has been achieved by estimating the sample mean and its standard error from each study that reports a median in order…
Multivariate meta-analysis can be adapted to a wide range of situations for multiple outcomes and multiple treatment groups when combining studies together. The within-study correlation between effect sizes is often assumed known in multivariate meta-analysis while it is not always known practically. In this paper, we propose a generic method to approximate the within-study covariance for effect sizes in multivariate meta-analysis and apply this method to the scenarios with multiple outcomes and one outcome with multiple treatment groups respectively.
Impact of clinical decision support systems (cdss) on clinical outcomes and healthcare delivery in low- and middle-income countries: protocol for a systematic review and meta-analysis
ICMR National Institute for Research in Digital Health & Data Science（印度国家数字健康与数据科学研究所）；ICMR Headquarters（印度国家医学研究委员会总部）；ICMR-RMRC Bhubaneshwar（印度国家医学研究委员会比哈尔邦研究中心）
Causally Interpretable Meta-Mediation Analysis With Missing At Random Mediator and Outcome Data
EPILOGY, Institut Mondor of Biomedical Research, INSERM U955（INSERM U955 蒙多尔生物医学研究所 EPILOGY）；Université Paris-Est Créteil（巴黎东克雷泰伊大学）；Mines Paris, Université Paris Sciences Lettres（巴黎矿业学院，巴黎文理研究大学）；Department of Mathematics, Université du Québec à Montréal（蒙特利尔大学数学系）
Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early…
Enrichment of predictive models with new biomolecular markers is an important task in high-dimensional omic applications. Increasingly, clinical studies include several sets of such omics markers available for each patient, measuring different levels of biological variation. As a result, one of the main challenges in predictive research is the integration of different sources of omic biomarkers for the prediction of health traits. We review several approaches for the combination of omic markers in the context of binary outcome prediction, all based on double cross-validation and regularized re…
We present methods for causally interpretable meta-analyses that combine information from multiple randomized trials to estimate potential (counterfactual) outcome means and average treatment effects in a target population. We consider identifiability conditions, derive implications of the conditions for the law of the observed data, and obtain identification results for transporting causal inferences from a collection of independent randomized trials to a new target population in which experimental data may not be available. We propose an estimator for the potential (counterfactual) outcome m…
We propose a distributed quadratic inference function framework to jointly estimate regression parameters from multiple potentially heterogeneous data sources with correlated vector outcomes. The primary goal of this joint integrative analysis is to estimate covariate effects on all outcomes through a marginal regression model in a statistically and computationally efficient way. We develop a data integration procedure for statistical estimation and inference of regression parameters that is implemented in a fully distributed and parallelized computational scheme. To overcome computational and…
Motivated by two case studies using primary care records from the Clinical Practice Research Datalink, we describe statistical methods that facilitate the analysis of tall data, with very large numbers of observations. Our focus is on investigating the association between patient characteristics and an outcome of interest, while allowing for variation among general practices. We explore ways to fit mixed effects models to tall data, including predictors of interest and confounding factors as covariates, and including random intercepts to allow for heterogeneity in outcome among practices. We i…
Multivariate meta-analysis is gaining prominence in evidence synthesis research because it enables simultaneous synthesis of multiple correlated outcome data, and random-effects models have generally been used for addressing between-studies heterogeneities. However, coverage probabilities of confidence regions or intervals for standard inference methods for random-effects models (e.g., restricted maximum likelihood estimation) cannot retain their nominal confidence levels in general, especially when the number of synthesized studies is small because their validities depend on large sample appr…
