The current meta-analytic structural equation modeling (MASEM) techniques cannot properly deal with cases where there are multiple effect sizes available for the same relationship from the same study. Existing applications either treat these effect sizes as independent, randomly select one effect size amongst many, or create an average effect size. None of these approaches deal with the inherent dependency in effect sizes, and either leads to biased estimates or loss of information and power. An alternative technique is to use univariate three-level modeling in the two-stage approach to model these dependencies. These different strategies for dealing with dependent effect sizes in the context of MASEM have not been previously compared in a simulation study. This study aims to compare the performance of these strategies across different conditions; varying the number of studies, the number of dependent effect sizes within studies, the correlation between the dependent effect sizes, the magnitude of the path coefficient, and the between-studies variance. We examine the relative bias in parameter estimates and standard errors, coverage proportions of confidence intervals, as well as mean standard error and power as measures of efficiency. The results suggest that there is not one method that performs well across all these criteria, pointing to the need for better methods.

When conducting a systematic review, screening the vast body of literature to identify the small set of relevant studies is a labour-intensive and error-prone process. Although there is an increasing number of fully automated tools for screening, their performance is suboptimal and varies substantially across review topic areas. Many of these tools are only trained on small datasets, and most are not tested on a wide range of review topic areas. This study presents two systematic review datasets compiled from more than 8600 systematic reviews and more than 540000 abstracts covering 51 research topic areas in health and medical research. These datasets are the largest of their kinds to date. We demonstrate their utility in training and evaluating language models for title and abstract screening. Our dataset includes detailed metadata of each review, including title, background, objectives and selection criteria. We demonstrated that a small language model trained on this dataset with additional metadata has excellent performance with an average recall above 95% and specificity over 70% across a wide range of review topic areas. Future research can build on our dataset to further improve the performance of fully automated tools for systematic review title and abstract screening.

Unanchored population-adjusted indirect comparisons (PAICs) such as matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) attracted a significant attention in the health technology assessment field in recent years. These methods allow for indirect comparisons by balancing different patient characteristics in single-arm studies in the case where individual patient-level data are only available for one study. However, the validity of findings from unanchored MAIC/STC analyses is frequently questioned by decision makers, due to the assumption that all potential prognostic factors and effect modifiers are accounted for. Addressing this critical concern, we introduce a sensitivity analysis algorithm for unanchored PAICs by extending quantitative bias analysis techniques traditionally used in epidemiology. Our proposed sensitivity analysis involves simulating important covariates that were not reported by the comparator study when conducting unanchored STC and enables the formal evaluating of the impact of unmeasured confounding in a quantitative manner without additional assumptions. We demonstrate the practical application of this method through a real-world case study of metastatic colorectal cancer, highlighting its utility in enhancing the robustness and credibility of unanchored PAIC results. Our findings emphasise the necessity of formal quantitative sensitivity analysis in interpreting unanchored PAIC results, as it quantifies the robustness of conclusions regarding potential unmeasured confounders and supports more robust, reliable, and informative decision-making in healthcare.

Network meta-analysis (NMA) enables simultaneous assessment of multiple treatments by combining both direct and indirect evidence. While NMAs are increasingly important in healthcare decision-making, challenges remain due to limited direct comparisons between treatments. This data sparsity complicates the accurate estimation of correlations among treatments in arm-based NMA (AB-NMA). To address these challenges, we introduce a novel sensitivity analysis tool tailored for AB-NMA. This study pioneers a tipping point analysis within a Bayesian framework, specifically targeting correlation parameters to assess their influence on the robustness of conclusions about relative treatment effects. The analysis explores changes in the conclusion based on whether the 95% credible interval includes the null value (referred to as the interval conclusion) and the magnitude of point estimates. Applying this approach to multiple NMA datasets, including 112 treatment pairs, we identified tipping points in 13 pairs (11.6%) for interval conclusion change and in 29 pairs (25.9%) for magnitude change with a threshold at 15%. These findings underscore potential commonality in tipping points and emphasize the importance of our proposed analysis, especially in networks with sparse direct comparisons or wide credible intervals for correlation estimates. A case study provides a visual illustration and interpretation of the tipping point analysis. We recommend integrating this tipping point analysis as a standard practice in AB-NMA.

The importance of network meta-analysis (NMA) methods for time-to-event (TTE) that do not rely on the proportional hazard (PH) assumption is increasingly recognized in oncology, where clinical trials evaluating new interventions versus standard comparators often violate this assumption. However, existing NMA methods that allow for time-varying treatment effects do not directly leverage individual events and censor times that can be reconstructed from Kaplan–Meier curves, which may be more accurate than discrete hazards. They are also challenging to implement given reparameterizations that rely on discrete hazards. Additionally, two-step methods require assumptions regarding within-study normality and variance. We propose a one-step fully Bayesian parametric individual patient data (IPD)-NMA model that fits TTE data with the exact likelihood and allows for time-varying treatment effects. We define fixed or random effects with the following distributions: Weibull, Gompertz, log-normal, log-logistic, gamma, or generalized gamma distributions. We apply the one-step model to a network of randomized controlled trials (RCTs) evaluating multiple interventions for advanced melanoma and compare results with those obtained with the two-step approach. Additionally, a simulation study was performed to compare the proposed one-step method to the two-step method. The one-step method allows for straightforward model selection among the “standard” distributions, now including gamma and generalized gamma, with treatment effects on either the scale alone or with multivariate treatment effects. Generalized gamma offers flexibility to model U-shaped hazards within a network of RCTs, with accessible interpretation of parameters that simplifies to exponential, Weibull, log-normal, or gamma in special cases.

Graphical displays are often utilised for high-quality reporting of meta-analyses. Previous work has presented augmentations to funnel plots that assess the impact that an additional trial would have on an existing meta-analysis. However, decision-makers, such as the National Institute for Health and Care Excellence in the United Kingdom, assess health technologies based on their cost-effectiveness, as opposed to efficacy alone. Motivated by this fact, this article outlines a novel approach, developed for augmenting funnel plots, based on the ability of an additional trial to change a decision regarding the optimal intervention. The approach is presented for a generalised class of economic decision models, where the clinical effectiveness of the health technology of interest is informed by a meta-analysis, and is illustrated with an example application. The ‘decision contours’ produced from the proposed methods have various potential uses not only for decision-makers and research funders but also for other researchers, such as meta-analysts and primary researchers designing new studies, as well as those developing health technologies, such as pharmaceutical companies. The relationship between the new approach and existing methods for determining sample size calculations for future trials is also considered.

In small meta-analyses (e.g., up to 20 studies), the best-performing frequentist methods can yield very wide confidence intervals for the meta-analytic mean, as well as biased and imprecise estimates of the heterogeneity. We investigate the frequentist performance of alternative Bayesian methods that use the invariant Jeffreys prior. This prior has the usual Bayesian motivation, but also has a purely frequentist motivation: the resulting posterior modes correspond to the established Firth bias correction of the maximum likelihood estimator. We consider two forms of the Jeffreys prior for random-effects meta-analysis: the previously established “Jeffreys1” prior treats the heterogeneity as a nuisance parameter, whereas the “Jeffreys2” prior treats both the mean and the heterogeneity as estimands of interest. In a large simulation study, we assess the performance of both Jeffreys priors, considering different types of Bayesian estimates and intervals. We assess point and interval estimation for both the mean and the heterogeneity parameters, comparing to the best-performing frequentist methods. For small meta-analyses of binary outcomes, the Jeffreys2 prior may offer advantages over standard frequentist methods for point and interval estimation of the mean parameter. In these cases, Jeffreys2 can substantially improve efficiency while more often showing nominal frequentist coverage. However, for small meta-analyses of continuous outcomes, standard frequentist methods seem to remain the best choices. The best-performing method for estimating the heterogeneity varied according to the heterogeneity itself. Röver & Friede’s R package bayesmeta implements both Jeffreys priors. We also generalize the Jeffreys2 prior to the case of meta-regression.

In prognosis studies with time-to-event outcomes, the survivals of groups with high/low biomarker expression are often estimated by the Kaplan–Meier method, and the difference between groups is measured by the hazard ratios (HRs). Since the high/low expressions are usually determined by study-specific cutoff values, synthesizing only HRs for summarizing the prognostic capacity of a biomarker brings heterogeneity in the meta-analysis. The time-dependent summary receiver operating characteristics (SROC) curve was proposed as a cutoff-free summary of the prognostic capacity, extended from the SROC curve in meta-analysis of diagnostic studies. However, estimates of the time-dependent SROC curve may be threatened by reporting bias in that studies with significant outcomes, such as HRs, are more likely to be published and selected in meta-analyses. Under this conjecture, this paper proposes a sensitivity analysis method for quantifying and adjusting reporting bias on the time-dependent SROC curve. We model the publication process determined by the significance of the HRs and introduce a sensitivity analysis method based on the conditional likelihood constrained by some expected proportions of published studies. Simulation studies showed that the proposed method could reduce reporting bias given the correctly-specified marginal selection probability. The proposed method is illustrated on the real-world meta-analysis of Ki67 for breast cancer.

Model-based recursive partitioning (MOB) and its extension, metaMOB, are tools for identifying subgroups with differential treatment effects. When pooling data from various trials the metaMOB approach uses random effects to model the heterogeneity of treatment effects. In situations where interventions offer only small overall benefits and require extensive, costly trials with a large participant enrollment, leveraging individual-participant data (IPD) from multiple trials can help identify individuals who are most likely to benefit from the intervention. We explore the application of MOB and metaMOB in the context of non-specific low back pain treatment, using synthetic data based on a subset of the individual participant data meta-analysis by Patel et al.1 Our study underscores the need to explore heterogeneity in intercepts and treatment effects to identify subgroups with differential treatment effects in IPD meta-analyses.

Effect modification occurs when a covariate alters the relative effectiveness of treatment compared to control. It is widely understood that, when effect modification is present, treatment recommendations may vary by population and by subgroups within the population. Population-adjustment methods are increasingly used to adjust for differences in effect modifiers between study populations and to produce population-adjusted estimates in a relevant target population for decision-making. It is also widely understood that marginal and conditional estimands for non-collapsible effect measures, such as odds ratios or hazard ratios, do not in general coincide even without effect modification. However, the consequences of both non-collapsibility and effect modification together are little-discussed in the literature.

In this article, we set out the definitions of conditional and marginal estimands, illustrate their properties when effect modification is present, and discuss the implications for decision-making. In particular, we show that effect modification can result in conflicting treatment rankings between conditional and marginal estimates. This is because conditional and marginal estimands correspond to different decision questions that are no longer aligned when effect modification is present. For time-to-event outcomes, the presence of covariates implies that marginal hazard ratios are time-varying, and effect modification can cause marginal hazard curves to cross. We conclude with practical recommendations for decision-making in the presence of effect modification, based on pragmatic comparisons of both conditional and marginal estimates in the decision target population. Currently, multilevel network meta-regression is the only population-adjustment method capable of producing both conditional and marginal estimates, in any decision target population.

We developed a geographic search filter for retrieving studies about Germany from PubMed. In this study, we aimed to translate and validate it for use in Embase and MEDLINE(R) ALL via Ovid. Adjustments included aligning PubMed field tags with Ovid’s syntax, adding a keyword heading field for both databases, and incorporating a correspondence address field for Embase. To validate the filters, we used systematic reviews (SRs) that included studies about Germany without imposing geographic restrictions on their search strategies. Subsequently, we conducted (i) case studies (CSs), applying the filters to the search strategies of the 17 eligible SRs; and (ii) aggregation studies, combining the SRs’ search strategies with the ‘OR’ operator and applying the filters. In the CSs, the filters demonstrated a median sensitivity of 100% in both databases, with interquartile ranges (IQRs) of 100%–100% in Embase and 93.75%–100% in MEDLINE(R) ALL. Median precision improved from 0.11% (IQR: 0.05%–0.30%) to 1.65% (IQR: 0.78%–3.06%) and from 0.19% (IQR: 0.11%–0.60%) to 5.13% (IQR: 1.77%–6.85%), while the number needed to read (NNR) decreased from 893.40 (IQR: 354.81–2,219.58) to 60.44 (IQR: 33.94–128.97) and from 513.29 (IQR: 167.35–930.99) to 19.50 (IQR: 14.66–59.35) for Embase and MEDLINE(R) ALL, respectively. In the aggregation studies, the overall sensitivities were 98.19% and 97.14%, with NNRs of 83.29 and 33.34 in Embase and MEDLINE(R) ALL, respectively. The new Embase and MEDLINE(R) ALL filters for Ovid reliably retrieve studies about Germany, enhancing search precision. The approach described in our study can support search filter developers in translating filters for various topics and contexts.

Machine learning (ML) models have been developed to identify randomised controlled trials (RCTs) to accelerate systematic reviews (SRs). However, their use has been limited due to concerns about their performance and practical benefits. We developed a high-recall ensemble learning model using Cochrane RCT data to enhance the identification of RCTs for rapid title and abstract screening in SRs and evaluated the model externally with our annotated RCT datasets. Additionally, we assessed the practical impact in terms of labour time savings and recall improvement under two scenarios: ML-assisted double screening (where ML and one reviewer screened all citations in parallel) and ML-assisted stepwise screening (where ML flagged all potential RCTs, and at least two reviewers subsequently filtered the flagged citations). Our model achieved twice the precision compared to the existing SVM model while maintaining a recall of 0.99 in both internal and external tests. In a practical evaluation with ML-assisted double screening, our model led to significant labour time savings (average 45.4%) and improved recall (average 0.998 compared to 0.919 for a single reviewer). In ML-assisted stepwise screening, the model performed similarly to standard manual screening but with average labour time savings of 74.4%. In conclusion, compared with existing methods, the proposed model can reduce workload while maintaining comparable recall when identifying RCTs during the title and abstract screening stages, thereby accelerating SRs. We propose practical recommendations to effectively apply ML-assisted manual screening when conducting SRs, depending on reviewer availability (ML-assisted double screening) or time constraints (ML-assisted stepwise screening).

The treatment recommendation based on a network meta-analysis (NMA) is usually the single treatment with the highest expected value (EV) on an evaluative function. We explore approaches that recommend multiple treatments and that penalise uncertainty, making them suitable for risk-averse decision-makers. We introduce loss-adjusted EV (LaEV) and compare it to GRADE and three probability-based rankings. We define properties of a valid ranking under uncertainty and other desirable properties of ranking systems. A two-stage process is proposed: the first identifies treatments superior to the reference treatment; the second identifies those that are also within a minimal clinically important difference (MCID) of the best treatment. Decision rules and ranking systems are compared on stylised examples and 10 NMAs used in NICE (National Institute of Health and Care Excellence) guidelines. Only LaEV reliably delivers valid rankings under uncertainty and has all the desirable properties. In 10 NMAs comparing between 5 and 41 treatments, an EV decision maker would recommend 4–14 treatments, and LaEV 0–3 (median 2) fewer. GRADE rules give rise to anomalies, and, like the probability-based rankings, the number of treatments recommended depends on arbitrary probability cutoffs. Among treatments that are superior to the reference, GRADE privileges the more uncertain ones, and in 3/10 cases, GRADE failed to recommend the treatment with the highest EV and LaEV. A two-stage approach based on MCID ensures that EV- and LaEV-based rules recommend a clinically appropriate number of treatments. For a risk-averse decision maker, LaEV is conservative, simple to implement, and has an independent theoretical foundation.

When conducting overviews of reviews, investigators must measure and describe the extent to which included systematic reviews (SRs) contain the same primary studies. The corrected covered area (CCA) quantifies overlap by counting primary studies included across a set of SRs. In this article, we introduce a modification to the CCA, the weighted CCA (wCCA), which accounts for differences in information contributed by primary studies. The wCCA adjusts the original CCA by weighting studies based on the square roots of their sample sizes. By weighting primary studies according to their precision, wCCA provides a useful and complementary representation of overlap in evidence syntheses .

Matching-adjusted indirect comparison (MAIC) has been increasingly applied in health technology assessments (HTA). By reweighting subjects from a trial with individual participant data (IPD) to match the summary statistics of covariates in another trial with aggregate data (AgD), MAIC enables a comparison of the interventions for the AgD trial population. However, when there are imbalances in effect modifiers with different magnitudes of modification across treatments, contradictory conclusions may arise if MAIC is performed with the IPD and AgD swapped between trials. This can lead to the “MAIC paradox,” where different entities reach opposing conclusions about which treatment is more effective, despite analyzing the same data. In this paper, we use synthetic data to illustrate this paradox and emphasize the importance of clearly defining the target population in HTA submissions. Additionally, we recommend making de-identified IPD available to HTA agencies, enabling further indirect comparisons that better reflect the overall population represented by both IPD and AgD trials, as well as other relevant target populations for policy decisions. This would help ensure more accurate and consistent assessments of comparative effectiveness.

Results of meta-analyses are of interest not only to researchers but often to policy-makers and other decision-makers (e.g., in education and medicine), and visualizations play an important role in communicating data and statistical evidence to the broader public. Therefore, the potential audience of meta-analytic visualizations is broad. However, the most common meta-analytic visualization – the forest plot – uses non-optimal design principles that do not align with data visualization best practices and relies on statistical knowledge and conventions not likely to be familiar to a broad audience. Previously, the Meta-Analytic Rain Cloud (MARC) plot has been shown to be an effective alternative to a forest plot when communicating the results of a small meta-analysis to education practitioners. However, the original MARC plot design was not well-suited for meta-analyses with large numbers of effect sizes as is common across the social sciences. This paper presents an extension of the MARC plot, intended for effective communication of moderate to large meta-analyses (k = 10, 20, 50, 100 studies). We discuss the design principles of the MARC plot, grounded in the data visualization and cognitive science literature. We then present the methods and results of a randomized survey experiment to evaluate the revised MARC plot in comparison to the original MARC plot, the forest plot, and a bar plot. We find that the revised MARC plot is more effective for communicating moderate to large meta-analyses to non-research audiences, offering a 0.30, 0.34, and 1.07 standard deviation improvement in chart users’ scores compared to the original MARC plot, forest plot, and bar plot, respectively.

Understanding causality is crucial for social scientific research to develop strong theories and inform practice. However, explicit discussion of causality is often lacking in social science literature due to ambiguous causal language. This paper introduces a text mining model fine-tuned to extract causal sentences from full-text social science papers. A dataset of 529 causal and 529 non-causal sentences manually annotated from the Cooperation Databank (CoDa) was curated to train and evaluate the model. Several pre-trained language models (BERT, SciBERT, RoBERTa, LLAMA, and Mistral) were fine-tuned on this dataset and general-purpose causality datasets. Model performance was evaluated on held-out social science and general-purpose test sets. Results showed that fine-tuning transformer models on the social science dataset significantly improved causal sentence extraction, even with limited data, compared to the models fine-tuned only on the general-purpose data. Results indicate the importance of domain-specific fine-tuning and data for accurately capturing causal language in academic writing. This automated causal sentence extraction method enables comprehensive, large-scale analysis of causal claims across the social sciences. By systematically cataloging existing causal statements, this work lays the foundation for further research to uncover the mechanisms underlying social phenomena, inform theory development, and strengthen the methodological rigor of the field.