Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies

Background: Standard random-effects meta-analysis methods perform poorly when applied to few studies only. Such settings however are commonly encountered in practice. It is unclear, whether or to what extent small-sample-size behaviour can be improved by more sophisticated modeling. Methods: We consider likelihood-based methods, the DerSimonian-Laird approach, Empirical Bayes, several adjustment methods and a fully Bayesian approach. Confidence intervals are based on a normal approximation, or on adjustments based on the Student-t-distribution. In addition, a linear mixed model and two generalized linear mixed models (GLMMs) assuming binomial or Poisson distributed numbers of events per study arm are considered for pairwise binary meta-analyses. We extract an empirical data set of 40 meta-analyses from recent reviews published by the German Institute for Quality and Efficiency in Health Care (IQWiG). Methods are then compared empirically as well as in a simulation study, based on few studies, imbalanced study sizes, and considering odds-ratio (OR) and risk ratio (RR) effect sizes. Coverage probabilities and interval widths for the combined effect estimate are evaluated to compare the different approaches. Results: Empirically, a majority of the identified meta-analyses include only 2 studies. Variation of methods or effect measures affects the estimation results. In the simulation study, coverage probability is, in the presence of heterogeneity and few studies, mostly below the nominal level for all frequentist methods based on normal approximation, in particular when sizes in meta-analyses are not balanced, but improve when confidence intervals are adjusted. Bayesian methods result in better coverage than the frequentist methods with normal approximation in all scenarios, except for some cases of very large heterogeneity where the coverage is slightly lower. Credible intervals are empirically and in the simulation study wider than unadjusted confidence intervals, but considerably narrower than adjusted ones, with some exceptions when considering RRs and small numbers of patients per trial-arm. Confidence intervals based on the GLMMs are, in general, slightly narrower than those from other frequentist methods. Some methods turned out impractical due to frequent numerical problems. Conclusions: In the presence of between-study heterogeneity, especially with unbalanced study sizes, caution is needed in applying meta-analytical methods to few studies, as either coverage probabilities might be compromised, or intervals are inconclusively wide. Bayesian estimation with a sensibly chosen prior for between-trial heterogeneity may offer a promising compromise

The Increase in Hemoglobin Concentration With Altitude Differs Between World Regions and Is Less in Children Than in Adults

To compensate for decreased oxygen partial pressure, high-altitude residents increase hemoglobin concentrations [Hb]. The elevation varies between world regions, posing problems in defining cutoff values for anemia or polycythemia. The currently used altitude adjustments (World Health Organization [WHO]), however, do not account for regional differences. Data from The Demographic and Health Survey (DHS) Program were analyzed from 32 countries harboring >4% of residents at altitudes above 1000 m. [Hb]-increase, (ΔHb/km altitude) was calculated by linear regression analysis. Tables show 95% reference intervals (RIs) for different altitude ranges, world regions, and age groups. The prevalence of anemia and polycythemia was calculated using regressions in comparison to WHO adjustments. The most pronounced Δ[Hb]/km was found in East Africans and South Americans while [Hb] increased least in South/South-East Asia. In African regions and Middle East, [Hb] was decreased in some altitude regions showing inconsistent changes in different age groups. Of note, in all regions, the Δ[Hb]/km was lower in children than in adults, and in the Middle East, it was even negative. Overall, the Δ[Hb]/km from our analysis differed from the region-independent adjustments currently suggested by the WHO resulting in a lower anemia prevalence at very high altitudes. The distinct patterns of Δ[Hb] with altitude in residents from different world regions imply that one single, region-independent correction factor for altitude is not be applicable for diagnosing abnormal [Hb]. Therefore, we provide regression coefficients and reference-tables that are specific for world regions and altitude ranges to improve diagnosing abnormal [Hb]

Adverse drug reactions associated with amitriptyline - protocol for a systematic multiple-indication review and meta-analysis

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-thecounter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including <100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using metaregression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. Discussion: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations

Left ventricular function, congestion, and effect of empagliflozin on heart failure risk after myocardial infarction

Background Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). Objective To evaluate the association between left ventricular ejection fraction (LVEF), congestion, or both on outcomes and the impact of empagliflozin in reducing HF risk post-MI. Methods In the EMPACT-MI trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF&lt;45%, congestion, or both to empagliflozin 10 mg daily or placebo and followed for a median of 17.9 months. Results Among 6522 patients, the mean baseline LVEF was 41%+9%; 2648 patients (40.6%) presented with LVEF&lt;45% alone, 1483 (22.7%) presented with congestion alone, and 2181 (33.4%) presented with both. Among patients in the placebo arm, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (hazard ratio [HR] 1.49; 95%CI, 1.31-1.69; P&lt;0.0001), first HF hospitalization (HR, 1.64; 95%CI, 1.37-1.96; P&lt;0.0001), and total HF hospitalizations (rate ratio [RR], 1.89; 95%CI, 1.51-2.36; P&lt;0.0001). Presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR 1.52, 1.94, and RR 2.03, respectively). Empagliflozin reduced the risk for first (HR 0.77, 95%CI 0.60-0.98) and total (RR 0.67, 95%CI 0.50-0.89) HF hospitalization, irrespective of LVEF or congestion or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. Conclusions In patients with AMI, severity of LV dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion

Effect of empagliflozin on heart failure outcomes after acute myocardial infarction: insights from the EMPACT-MI trial

Background: Empagliflozin reduces the risk of heart failure events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, and in those with prevalent heart failure irrespective of ejection fraction. While EMPACT-MI showed empagliflozin does not reduce the risk of the composite of hospitalization of heart failure and all-cause mortality, the impact of empagliflozin on first and recurrent heart failure events in patients after myocardial infarction is unknown. Methods: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for heart failure based on newly developed left ventricular ejection fraction of &lt;45% and/or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for heart failure outcomes. Results: Over a median of follow-up of 17.9 months, the risk for first heart failure hospitalization and total heart failure hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 (3.6%) vs. 153 (4.7%) patients with events, HR 0.77 [95% CI 0.60, 0.98], P=0.031 for first heart failure hospitalization and 148 vs. 207 events, RR 0.67 [95% CI 0.51, 0.89], P=0.006 for total heart failure hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total heart failure hospitalizations. Post-discharge need for new use of diuretics, renin-angiotensin modulators, and mineralocorticoid receptor antagonists were less in patients randomized to empagliflozin than placebo (all p&lt;0.05). Conclusions: In patients after acute myocardial infarction with left ventricular dysfunction or congestion, empagliflozin reduced the risk of heart failure

Meta-analysis data extracted from IQWiG publications

This data set contains data on 40 meta-analyses extracted from publications by the German Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; IQWiG). In April 2017, IQWiG publications were screened chronologically, starting with the most recent one. Each publication was searched for reported meta-analyses involving binary endpoints, and non-zero event counts in all study arms, and the first qualifying analysis within each report was entered into the database. The search was continued (going back to March 2012) until a total of 40 analyses had been found. For more details see also the related publication referenced below (Seide et al., 2018). The data set consists of two CSV files; the first one, IQWiG-metadata.csv, contains metadata regarding each of the 40 meta-analyses; these are in particular the following variables (columns): no: running number identifier: IQWiG project identifier date: publication date of IQWiG project report endpoint: name of endpoint page: page number in IQWiG project report studies: number of studies included in the meta-analysis effect.measure: effect measure used The second file, IQWiG-data.csv, contains the actual count data from 131 individual studies that went into the 40 meta-analyses (each row corresponding to a study that was meta-analysed, and several rows corresponding to each meta-analysis). It contains the following variables (columns): no: running number identifier: IQWiG project identifier study: study label treat.events: number of events in the treatment group treat.total: total number of cases in the treatment group control.events: number of events in the control group control.total: total number of cases in the control group Running number and identifier allow to match the entries from both files. </p

Recurrence of Equinus Foot in Cerebral Palsy following Its Correction&mdash;A Meta-Analysis

Background: Recurrence in cerebral palsy (CP) patients who have undergone operative or non-operative correction varies greatly from one study to another. Therefore, we conducted this meta-analysis to determine the pooled rate of equinus recurrence following its correction either surgically or non-surgically. Methods: Nine electronic databases were searched from inception to 6 May 2021, and the search was updated on 13 August 2021. We included all studies that reported the recurrence rate of equinus following its correction among CP patients. The primary outcome was recurrence, where data were reported as a pooled event (PE) rate and its corresponding 95% confidence interval (CI). We used the Cochrane&rsquo;s risk of bias (RoB-II) tool and ROBINS-I tool to assess the quality of included randomized and non-randomized trials, respectively. We conducted subgroup analyses to identify the sources of heterogeneity. Results: The overall rate of recurrence was 0.15 (95% CI: 0.05&ndash;0.18; I2 = 88%; p &lt; 0.01). Subgroup analyses indicated that the laterality of CP, study design, and intervention type were significant contributors to heterogeneity. The recurrence rate of equinus differed among interventions; it was highest in the multilevel surgery group (PE = 0.27; 95% CI: 0.19&ndash;0.38) and lowest in the Ilizarov procedure group (PE = 0.10; 95% CI: 0.04&ndash;0.24). Twelve studies had a low risk of bias, eight had a moderate risk, and nine had a serious risk of bias. Conclusion: The recurrence of equinus following its correction, either surgically or non-surgically, in CP patients is notably high. However, due to the poor quality of available evidence, our findings should be interpreted with caution. Future studies are still warranted to determine the actual risk of equinus recurrence in CP

Is the Prevalence of Equinus Foot in Cerebral Palsy Overestimated? Results from a Meta-Analysis of 4814 Feet

Background: Equinus is a common foot deformity in patients with cerebral palsy (CP). However, its prevalence is scarcely reported in the literature. Therefore, we conducted this review to estimate the prevalence of equinus foot in CP. Methods: Eight databases were searched. Our primary outcome was the prevalence of equinus foot in CP patients. Subgroup analysis was conducted based on study design, the laterality of CP, and whether equinus foot was defined or not. Results: The prevalence of equinus foot in CP was 93% (95% CI: 71–99). The prevalence was 99% (95% CI: 55–100), 96% (95% CI: 57–100), and 65% (95% CI: 37–86) in unilateral, both, and bilateral CP, respectively. Based on study design, equinus foot prevalence was 92% (95% CI: 34–100) in case series and 62% (95% CI: 47–74) in cohort studies. Four studies reported definition criteria for equinus foot, with a pooled prevalence rate of equinus foot of 99% (95% CI: 36–100) compared to a rate of 89% (95% CI: 59–98) among studies that lacked a definition criterion. Conclusions: This is the first meta-analysis to address the prevalence of equinus foot in CP patients. Although its prevalence is very high, our findings should be interpreted with caution due to the presence of multiple limitations, such as the lack of standardized definition criteria for equinus foot, the inappropriate study design, the wide confidence interval of equinus foot rate, and the small number of studies investigating it as a primary outcome

The Paris System for Reporting Urinary Cytology: A Meta-Analysis

The Paris System (TPS) for Reporting Urinary Cytology is a standardized, evidence-based reporting system, comprising seven diagnostic categories: nondiagnostic, negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), suspicious for high-grade urothelial carcinoma (SHGUC), HGUC, low-grade urothelial neoplasm (LGUN), and other malignancies. This study aimed to calculate the pooled risk of high-grade malignancy (ROHM) of each category and demonstrate the diagnostic accuracy of urine cytology reported with TPS. Four databases (PubMed, Embase, Scopus, Web of Science) were searched. Specific inclusion and exclusion criteria were applied, while data were extracted and analyzed both qualitatively and quantitatively. The pooled ROHM was 17.70% for the nondiagnostic category (95% CI, 0.0650; 0.3997), 13.04% for the NHGUC (95% CI, 0.0932; 0.1796), 38.65% for the AUC (95% CI, 0.3042; 0.4759), 12.45% for the LGUN (95% CI, 0.0431; 0.3101), 76.89 for the SHGUC (95% CI, 0.7063; 0.8216), and 91.79% for the HGUC and other malignancies (95% CI, 0.8722; 0.9482). A summary ROC curve was created and the Area Under the Curve (AUC) was 0.849, while the pooled sensitivity was 0.669 (95% CI, 0.589; 0.741) and false-positive rate was 0.101 (95% CI, 0.063; 0.158). In addition, the pooled DOR of the included studies was 21.258 (95% CI, 14.336; 31.522). TPS assigns each sample into a diagnostic category linked with a specific ROHM, guiding clinical management

The Increase in Hemoglobin Concentration With Altitude Differs Between World Regions and Is Less in Children Than in Adults

To compensate for decreased oxygen partial pressure, high-altitude residents increase hemoglobin concentrations [Hb]. The elevation varies between world regions, posing problems in defining cutoff values for anemia or polycythemia. The currently used altitude adjustments (World Health Organization [WHO]), however, do not account for regional differences. Data from The Demographic and Health Survey (DHS) Program were analyzed from 32 countries harboring >4% of residents at altitudes above 1000 m. [Hb]-increase, (ΔHb/km altitude) was calculated by linear regression analysis. Tables show 95% reference intervals (RIs) for different altitude ranges, world regions, and age groups. The prevalence of anemia and polycythemia was calculated using regressions in comparison to WHO adjustments. The most pronounced Δ[Hb]/km was found in East Africans and South Americans while [Hb] increased least in South/South-East Asia. In African regions and Middle East, [Hb] was decreased in some altitude regions showing inconsistent changes in different age groups. Of note, in all regions, the Δ[Hb]/km was lower in children than in adults, and in the Middle East, it was even negative. Overall, the Δ[Hb]/km from our analysis differed from the region-independent adjustments currently suggested by the WHO resulting in a lower anemia prevalence at very high altitudes. The distinct patterns of Δ[Hb] with altitude in residents from different world regions imply that one single, region-independent correction factor for altitude is not be applicable for diagnosing abnormal [Hb]. Therefore, we provide regression coefficients and reference-tables that are specific for world regions and altitude ranges to improve diagnosing abnormal [Hb]