Aggregate Data Meta-analysis Research Articles

Mortality and its risk factors in critically ill patients with connective tissue diseases: A meta-analysis

BackgroundSystemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM) and rheumatoid arthritis (RA) are connective tissue diseases (CTD) whose complications can lead to management in the intensive care unit (ICU). ObjectivesTo estimate by meta-analysis ICU mortality rates for CTD. MethodsA systematic literature review was performed to identify articles studying critically ill CTD patients. A random-effects model was chosen for analysis. Pooled proportion mortality was calculated using aggregated-data meta-analysis with a random-effects model and assessment of heterogeneity with the I2 statistic. Risk of bias was assessed using the quality assessment tool. ResultsOf the 5694 individual publications, a sample of 31 independent cohorts was used for the meta-analysis totalling 5007 patients. The main cause for admission was sepsis (43%) followed by “flare-ups” (40%). The overall pooled proportion of mortality of CTD patients across all 31 studies was 33% (95%CI: 28–38%). In the IIM subgroup and that of SSc, mortality was 70% (95%CI: 46–86%) and 40% (95%CI: 25–47%), respectively. In the SLE subgroup, mortality was similar to the overall pooled mortality of 35% (95%CI: 29–42%). Subgroup mortality for RA and pSS patients was respectively 20% (95%CI: 11–33%) and 17% (95%CI: 6–41%); lower than the overall pooled mortality. Heterogeneity in each subgroup remained high. ConclusionThe overall pooled proportion of mortality of ICU patients with CTD was 33% (95%CI: 28–38%), with a high heterogeneity (I2= 89%). In the subgroup analysis, mortality was higher for patients with IIM and SSc.

A Guide to Estimating the Reference Range From a Meta-Analysis Using Aggregate or Individual Participant Data.

Clinicians frequently must decide whether a patient's measurement reflects that of a healthy "normal" individual. Thus, the reference range is defined as the interval in which some proportion (frequently 95%) of measurements from a healthy population is expected to fall. One can estimate it from a single study or preferably from a meta-analysis of multiple studies to increase generalizability. This range differs from the confidence interval for the pooled mean and the prediction interval for a new study mean in a meta-analysis, which do not capture natural variation across healthy individuals. Methods for estimating the reference range from a meta-analysis of aggregate data that incorporates both within- and between-study variations were recently proposed. In this guide, we present 3 approaches for estimating the reference range: one frequentist, one Bayesian, and one empirical. Each method can be applied to either aggregate or individual-participant data meta-analysis, with the latter being the gold standard when available. We illustrate the application of these approaches to data from a previously published individual-participant data meta-analysis of studies measuring liver stiffness by transient elastography in healthy individuals between 2006 and 2016.

Longer than 2 hours to antibiotics is associated with doubling of mortality in a multinational community-acquired bacterial meningitis cohort

To optimally define the association between time to effective antibiotic therapy and clinical outcomes in adult community-acquired bacterial meningitis. A systematic review of the literature describing the association between time to antibiotics and death or neurological impairment due to adult community-acquired bacterial meningitis was performed. A retrospective cohort, multivariable and propensity-score based analyses were performed using individual patient clinical data from Australian, Danish and United Kingdom studies. Heterogeneity of published observational study designs precluded meta-analysis of aggregate data (I2 = 90.1%, 95% CI 71.9–98.3%). Individual patient data on 659 subjects were made available for analysis. Multivariable analysis was performed on 180–362 propensity-score matched data. The risk of death (adjusted odds ratio, aOR) associated with treatment after two hours was 2.29 (95% CI 1.28–4.09) and increased substantially thereafter. Similarly, time to antibiotics of greater than three hours was associated with an increase in the occurrence of neurological impairment (aOR 1.79, 95% CI 1.03–3.14). Among patients with community-acquired bacterial meningitis, odds of mortality increase markedly when antibiotics are given later than two hours after presentation to the hospital.

Individual participant data meta-analysis versus aggregate data meta-analysis: A case study in eczema and food allergy prevention.

IntroductionMeta‐analysis traditionally uses aggregate data from published reports. Individual Participant Data (IPD) meta‐analysis, which obtains and synthesizes participant‐level data, is potentially more informative, but resource‐intensive. The impact on the findings of meta‐analyses using IPD in comparison with aggregate data has rarely been formally evaluated.MethodsWe conducted a secondary analysis of a Cochrane systematic review of skincare interventions for preventing eczema and food allergy in infants to identify the impact of the analytical choice on the review's findings. We used aggregate data meta‐analysis only and contrasted the results against those of the originally published IPD meta‐analysis. All meta‐analysis used random effects inverse variance models. Certainty of evidence was evaluated using GRADE.ResultsThe pooled treatment effects for the Cochrane systematic review's co‐primary outcomes of eczema and food allergy were similar in IPD meta‐analysis (eczema RR 1.03, 95% CI 0.81, 1.31; I241%, 7 studies 3075 participants), and aggregate meta‐analysis (eczema RR 1.01 95% CI 0.77, 1.33; I253%, 7 studies, 3089 participants). In aggregate meta‐analysis, the statistical heterogeneity could not be explained but using IPD it was explained by one trial which used a different, bathing intervention. For IPD meta‐analysis, risk of bias was assessed as lower and more adverse event data were available compared with aggregate meta‐analysis. This resulted in higher certainty of evidence, especially for adverse events. IPD meta‐analysis enabled analysis of treatment interactions by age and hereditary eczema risk; and analysis of the effect of treatment adherence using pooled complier‐adjusted‐causal‐effect analysis, none of which was possible in aggregate meta‐analysis.ConclusionsFor this systematic review, IPD did not significantly change primary outcome risk ratios compared with aggregate data meta‐analysis. However, certainty of evidence, safety outcomes, subgroup and adherence analyses were significantly different using IPD. This demonstrates benefits of adopting an IPD approach to meta‐analysis.

Handgrip strength and risk of cognitive outcomes: new prospective study and meta-analysis of 16 observational cohort studies

Handgrip strength (HGS), a measure of muscular strength, might be a risk indicator for cognitive functioning, but the evidence is not consistent. Using a new prospective study and meta-analysis of published observational cohort studies, we aimed to evaluate the prospective associations of HGS with poor cognitive outcomes including cognitive impairment, dementia and Alzheimer’s disease (AD). Handgrip strength, measured using a Martin-Balloon-Vigorimeter, was assessed at baseline in a population-based sample of 852 men and women with good cognitive function in the Kuopio Ischemic Heart Disease cohort. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for cognitive outcomes. Relevant published studies were sought in MEDLINE, Embase and Web of Science from inception until October 2021 and pooled using random effects meta-analysis. During a median follow-up of 16.6 years, 229 dementia cases were recorded. Comparing extreme tertiles of HGS, the multivariable adjusted HR (95% CI) for dementia, AD and vascular dementia was 0.77 (0.55–1.07), 0.75 (0.52–1.10) and 0.49 (0.16–1.48), respectively. In a meta-analysis of 16 population-based prospective cohort studies (including the current study) comprising 180,920 participants, the pooled multivariable adjusted relative risks (95% CIs) comparing the top vs bottom thirds of HGS levels were as follows: 0.58 (0.52–0.65) for cognitive impairment; 0.37 (0.07–1.85) for cognitive decline; 0.73 (0.62–0.86) for dementia; 0.68 (0.53–0.87) for AD; and 0.48 (0.32–0.73) for vascular dementia. GRADE quality of evidence ranged from low to very low. Meta-analysis of aggregate prospective data suggests that HGS may be a risk indicator for poor cognitive outcomes such as cognitive impairment, dementia and AD. Systematic review registration: PROSPERO 2021: CRD42021237750.

Prone Positioning in Patients With COVID-19: Analysis of Multicenter Registry Data and Meta-analysis of Aggregate Data.

Evidence suggests a beneficial effect of prone positioning (PP) in COVID-19. Meta-analysis of individual (7 investigators' groups) and aggregate data (PubMed/EMBASE) regarding the impact of PP on the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PO2/FiO2) in patients with COVID-19. Among 121 patients (mean age±SD 59.1±10.7 years, 55% males, 57% intubated) the mean post-versus pre- PP PO2/FiO2 difference was: (i) 50.4±64.3 mmHg, p<0.01, (ii) similar in awake (58.7±72.1 mmHg) versus intubated patients (44.1±57.5 mmHg, p=NS), (iii) inversely correlated with body mass index (r=-0.43, p<0.01). Meta-analysis of 23 studies (n=547, weighted age 58.3±4.1, 73% males, 59% intubated) showed a pooled PO2/FiO2 difference of 61.8 [95% confidence intervals=49.9-73.6] mmHg. Meta-regression analysis revealed no associations with baseline demographics, the time in PP before assessment, and the risk of bias of the studies. PP seems to improve oxygenation of patients with COVID-19.

Circulating Interleukin-6 Levels and Incident Ischemic Stroke: A Systematic Review and Meta-analysis of Prospective Studies.

Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. However, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. We set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population. Following the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored nonlinear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias. We identified 11 studies (n = 27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were female. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7-9). In meta-analyses, 1 SD increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (relative risk 1.19; 95% confidence interval 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias. Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

Efficacy and Safety of Artemisinin-Based Combination Therapy for the Treatment of Uncomplicated Malaria in Pregnant Women: A Systematic Review and Meta-Analysis.

IntroductionMalaria is one of the infectious diseases with substantial risks for pregnant women, the fetus and the newborn child. Thus, prevention and treatment of malaria with safe and effective drugs is of paramount importance. Pregnant women are mostly excluded from clinical trials, and systematic approaches of pharmacovigilance in pregnancy are limited. This means the safety and efficacy of antimalarial agents during pregnancy are unclear.PurposeThis study was designed to carry out a systematic review and aggregate data meta-analysis of literature published on efficacy and safety of artemisinin-based combination therapy (ACT) for uncomplicated malaria in pregnant women.MethodsA search of literature published between 1998 to 2020 on efficacy and safety of artemisinin-based combination therapy (ACT) in pregnant women was made using Cochrane Library, Medline and the Malaria in Pregnancy Consortium Library. Data were extracted independently by two reviewers, and any discrepancies were resolved by consensus. Meta-analysis was carried out using Open Meta-Analyst software. Random effects model was applied, and the heterogeneity of studies was evaluated using Higgins I2.ResultsTwenty-four studies that fulfilled the inclusion criteria were included in the final assessment. Overall, days 28 to 63 malaria treatment success rate was 96.1%. Overall days 28 to 63 cure rates for AL, AS+AQ, AS+MQ, DHA+PQ, AS+ATQ+PG and AS+SP were 95.1%, 92.2%, 97.0%,94.3%, 96.5% and 97.4%, respectively. Comparison of ACTs with non-ACTs revealed that the risk of treatment failure was substantially lower in patients treated with ACTs than with non-ACTs (risk ratio 0.20, 95% C.I. 0.09–0.43). The overall prevalences of miscarriage, stillbirth and congenital anomalies were 0.3%, 2.1% and 1.0%, respectively, and found to be comparable among various ACTs. There was comparable tolerability across ACTs during pregnancy.ConclusionACTs demonstrated a high cure rate, safety and tolerability against Plasmodium falciparum infection in pregnant women. The higher treatment success and comparable tolerability could be used as an input for decision makers to support the continued usage of ACTs for treatment of uncomplicated falciparum malaria in pregnant women.

Stroke Etiology and Outcomes after Endovascular Thrombectomy: Results from the SITS Registry and a Meta-Analysis.

Background and PurposeThe influence of stroke etiology on outcomes after endovascular thrombectomy (EVT) is not well understood. We aimed to investigate whether stroke etiology subgrouped as large artery atherosclerosis (LAA) and cardiac embolism (CE) influences outcomes in large artery occlusion (LAO) treated by EVT. MethodsWe included EVT treated LAO stroke patients registered in the Safe Implementation of Treatment in Stroke (SITS) thrombectomy register between January 1, 2014 and September 3, 2019. Primary outcome was successful reperfusion (modified Treatment in Cerebral Infarction 2b-3). Secondary outcomes were symptomatic intracranial hemorrhage (SICH), 3-month functional independence (modified Ranking Scale 0–2) and death. Multivariable logistic regression models were used for comparisons. In addition, a meta-analysis of aggregate data from the current literature was conducted (PROSPERO, ID 167447). ResultsOf 7,543 patients, 1,903 (25.2%) had LAA, 3,214 (42.6%) CE, and 2,426 (32.2%) unknown, other, or multiple etiologies. LAA patients were younger (66 vs. 74, P<0.001) and had lower National Institutes of Health Stroke Scale score at baseline (15 vs. 16, P<0.001) than CE patients. Multivariable analyses showed that LAA patients had lower odds of successful reperfusion (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.57 to 0.86) and functional independence (OR, 0.74; 95% CI, 0.63 to 0.85), higher risk of death (OR, 1.44; 95% CI, 1.21 to 1.71), but no difference in SICH (OR, 1.09; 95% CI, 0.71 to 1.66) compared to CE patients. The systematic review found 25 studies matching the criteria. The meta-analysis did not find any difference between etiologies. ConclusionsFrom the SITS thrombectomy register, we observed a lower chance of reperfusion and worse outcomes after thrombectomy in patients with LAA compared to CE etiology, despite more favorable baseline characteristics. In contrast, the meta-analysis did not find any difference between etiologies with aggregate data.

Individual Patient Data Meta-Analysis and Network Meta-Analysis.

Meta-analyses are often conducted using trial-level summary data. However, when individual patient data (IPD ) is available, there is greater flexibility in the analysis and a wider range of statistical models that can be fitted. There are two approaches to fitting IPD models. The traditional two-stage approach involves analyzing each trial individually in the first stage and then combining trial estimates of treatment effectiveness in the second stage using methods developed for aggregate data meta-analysis. Growing in popularity is the one-stage approach in which trials are analyzed and synthesized within one statistical model whilst the clustering of patients within trials is accounted for. This chapter outlines both fixed effect and random effects one- and two-stage meta-analysis models for continuous, binary, and time-to-event outcomes. The meta-analysis framework is then extended to the scenario where there are more than two treatments and network meta-analysis models are described.The availability of IPD provides greater statistical power for investigating interactions between treatments and covariates. Treatment-covariate interactions contain both within- and across-trial information where the across-trial information may be subject to ecological bias. This chapter presents network meta-analysis models separating out the within- and across-trial information and finishes by considering practical solutions for dealing with missing covariate data, assessing the consistency assumption, combining IPD and aggregate data and specific considerations for time-to-event outcomes.

Hemicraniectomy for Dominant vs Nondominant Middle Cerebral Artery Infarction: A Systematic Review and Meta-Analysis

ObjectivesDecompressive hemicraniectomy decreases mortality and severe disability from space-occupying middle cerebral artery infarction in selected patients. However, attitudes towards hemicraniectomy for dominant-hemispheric stroke have been hesitant. This systematic review and meta-analysis examines the association of stroke laterality with outcome after hemicraniectomy. Materials and methodsWe performed a systematic literature search up to 6th February 2020 to retrieve original articles about hemicraniectomy for space-occupying middle cerebral artery infarction that reported outcome in relation to laterality. The primary outcome was severe disability (modified Rankin Scale 4‒6 or 5‒6 or Glasgow Outcome Scale 1‒3) or death. A two-stage combined individual patient and aggregate data meta-analysis evaluated the association between dominant-lateralized stroke and (a) short-term (≤ 3 months) and (b) long-term (> 3 months) outcome. We performed sensitivity analyses excluding studies with sheer mortality outcome, second-look strokectomy, low quality, or small sample size, and comparing populations from North America/Europe vs Asia/South America. ResultsThe analysis included 51 studies (46 observational studies, one nonrandomized trial, and four randomized controlled trials) comprising 2361 patients. We found no association between dominant laterality and unfavorable short-term (OR 1.00, 95% CI 0.69‒1.45) or long-term (OR 1.01, 95% CI 0.76‒1.33) outcome. The results were unchanged in all sensitivity analyses. The grade of evidence was very low for short-term and low for long-term outcome. ConclusionsThis meta-analysis suggests that patients with dominant-hemispheric stroke have equal outcome after hemicraniectomy compared to patients with nondominant stroke. Despite the shortcomings of the available evidence, our results do not support withholding hemicraniectomy based on stroke laterality.

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

P–619 Oral dydrogesterone (OD) versus micronized vaginal progesterone (MVP) for luteal phase support (LPS) in IVF/ICSI: a double blind, cross-over, pharmacokinetic study

Abstract Study question How does the blood pharmacokinetic (PK) profile of OD/MVP differ after the first and last administration dose when used as LPS for fresh embryo transfer? Summary answer: The PK profile differed strongly between both LPS administration strategies with a more rapid absorption, metabolism and clearance of OD in comparison with MVP. What is known already Adequate LPS is crucial to achieve a successful pregnancy following ovarian stimulation (OS) and fresh embryo transfer. OD has been proven to be non-inferior compared to MVP in two phase III clinical trials. Additionally, a combined individual participant data and aggregate data meta-analysis showed an odds ratio in favor of OD for live birth. Little information is available on the PK of LPS strategies, leaving an important field unexplored. Individualization of LPS has recently gained more interest and insight into the PK of progestogens is essential to correctly interpret the potential impact of circulating hormone levels on reproductive outcomes. Study design, size, duration Twenty oocyte donors underwent two OS cycles followed by one week of LPS (OD or MVP) in a randomized, cross-over, double blind, double dummy fashion. As both dydrogesterone (D) and 20αdihydrodydrogesterone (DHD) are progestogenic, D, DHD and progesterone (P) plasma levels were established using a validated liquid chromatography tandem mass spectrometry assay in each cycle, on the 1st (single dose PK) and 8th day (multiple dose PK) of LPS (9 and 12 harvesting time-points, respectively). Participants/materials, setting, methods All oocyte donors were &amp;lt;35 years, had regular menstrual cycles, no intra-uterine contraceptive device, AMH within normal range and BMI ≤ 29 kg/m2. OS was performed in a GnRH antagonist protocol followed by dual triggering (1000U hCG + 0.2mg triptorelin) as soon as ≥ 3 follicles of 20mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg (Utrogestan®) or OD 10 mg (Duphaston®), both three times daily. Main results and the role of chance The mean (±SD) age of the subjects was 27.4 (± 3.8) years and BMI was 24.0 (±3.2) kg/m2. The mean (±SD) number of oocytes retrieved was 19.7 ±10. No adverse events were reported during the intake of the study medication. The PK results are best estimates as sampling was reduced compared to a formal PK study. Following the intake of the first dose of OD, the observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml (single dose). The Cmax for D and DHD was reached after 1.5 and 1.6 hours (=Tmax), respectively. On the 8th day of LPS the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD (multiple dose). For both, the observed Tmax was 1.5 hours. Following the intake of the first dose of MVP, the Cmax for P was 16 ng/mL with a Tmax of 4.2 hours. On the 8th day of LPS the first administration of that day showed a Cmax for P of 21 ng/mL with a Tmax of 7.3 hours. Although low, the role of chance could be influenced by the relatively low sampling numbers and frequency. Limitations, reasons for caution Peripheral concentrations do not necessarily reflect the steroidogenic effect on endometrial progesterone receptors. Extrapolation to clinical practice is therefore difficult, however, molecular analyses of endometrial tissue harvested within this study protocol are underway to investigate further pharmacodynamics and the progestogenic impact on endometrial receptivity during the embryo implantation period. Wider implications of the findings: This is the first study comparing OD/MVP pharmacokinetics in IVF/ICSI. Results suggest administration frequency to be as important as dose, definitely for OD, showing a rapid absorption/clearance. More studies are needed to investigate blood levels in relation to time of LPS administration, especially in (artificially prepared) FET and LPS individualization. Trial registration number EUDRACT 2018–000105–23

Early childhood development and parental training interventions in rural China: a systematic review and meta-analysis

IntroductionInadequate care during early childhood can lead to long-term deficits in skills. Parenting programmes that encourage investment in young children are a promising tool for improving early development outcomes and...

MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair. English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF). Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8-28.5%, p < 0.001) and NBF (26.1% MD; 10.3-41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20). Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies. Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs.

The association between diabetes and gastric cancer: results from the Stomach Cancer Pooling Project Consortium.

BackgroundPrior epidemiologic studies on the association between diabetes and gastric cancer risk provided inconclusive findings, while traditional, aggregate data meta-analyses were characterized by high between-study heterogeneity.ObjectiveTo investigate the association between type 2 diabetes and gastric cancer using data from the ‘Stomach Cancer Pooling (StoP) Project’, an international consortium of more than 30 case–control and nested case–control studies, which is large and provides harmonized definition of participants’ characteristics across individual studies. The data have the potential to minimize between-study heterogeneity and provide greater statistical power for subgroup analysis.MethodsWe included 5592 gastric cancer cases and 12 477 controls from 14 studies from Europe, Asia, North America, and South America in a two-stage individual-participant data meta-analysis. Random-effect models were used to estimate summary odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) by pooling study-specific ORs.ResultsWe did not find an overall association between diabetes and gastric cancer (pooled OR = 1.01, 95% CI, 0.94–1.07). However, the risk of cardia gastric cancer was significantly higher among individuals with type 2 diabetes (OR = 1.16, 95% CI, 1.02–1.33). There was no association between diabetes and gastric cancer risk in strata of Helicobacter pylori infection serostatus, age, sex, BMI, smoking status, alcohol consumption, fruit/vegetable intake, gastric cancer histologic type, and source of controls.ConclusionThis study provides additional evidence that diabetes is unrelated to gastric cancer overall but may be associated with excess cardia gastric cancer risk.

New insights in diagnostic thresholds for total serum bile acid in intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disorder known to be associated with fetal adverse events, in particular stillbirth. At present, an effective treatment to reduce the risk of stillbirth, does not exist. Ursodeoxycholic acid (UDCA) is often given in clinical practice to reduce maternal symptom of pruritus but without strong evidence (Walker KF et al. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7(7):CD000493), and iatrogenic preterm birth is induced when the risk of stillbirth is thought to be higher (Ovadia C et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet. 2019 Mar 2;393(10174):899-909).

Effects of Colchicine on Cardiovascular Outcomes in Patients with Coronary Artery Disease: A Systematic Review and One-Stage and Two-Stage Meta-Analysis of Randomized-Controlled Trials.

Colchicine has received emerging interest due to its cardiovascular benefits in patients with coronary artery disease (CAD). We conducted a one-stage meta-analysis of reconstructed individual patient data (IPD) from randomized-controlled trials to summarize the effects of colchicine on cardiovascular outcomes in patients with CAD. Four databases (PubMed, Embase, Cochrane, SCOPUS) were searched for articles published from inception to 30th September 2020, examining the effect of colchicine on cardiovascular outcomes in patients with CAD, yielding 10 randomized-controlled trials with a combined cohort of 12,781 patients. IPD was reconstructed from Kaplan-Meier curves published in 3 studies and analysed using the shared-frailty Cox model. Aggregate data meta-analysis of all 10 studies was performed for outcomes unsuitable for IPD reconstruction. In patients receiving colchicine compared to placebo, one-stage meta-analysis demonstrated a hazard ratio of 0.70 (95% CI 0.61-0.80) for the composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent hospitalization for angina requiring coronary revascularization. Aggregate data meta-analysis demonstrated a significant reduction in hazard rate for stroke (HR 0.45; 95% CI 0.27-0.75) and urgent revascularization (HR 0.59; 95% CI 0.38-0.91); and a relative risk reduction for myocardial infarction (RR 0.72; 95% CI of 0.52-1.00) and post-operative atrial fibrillation (RR 0.64; 95% CI 0.48-0.86). Given the significant benefits of colchicine demonstrated on IPD, and its consistent benefits when analyzed using aggregate data meta-analysis, we propose that colchicine may be considered as an additional pharmacological adjunct to the first line therapy for patients with coronary artery disease.

Using Machine Learning to Identify and Investigate Moderators of Alcohol Use Intervention Effects in Meta-Analyses.

To illustrate a machine learning-based approach for identifying and investigating moderators of alcohol use intervention effects in aggregate-data meta-analysis. We illustrated the machine learning technique of random forest modeling using data from an ongoing meta-analysis of brief substance use interventions implemented in general healthcare settings. A subset of 40 trials testing brief alcohol interventions (BAIs) was used; these trials provided 344 estimates of post-intervention effects on participants' alcohol use as well as data on 20 potential moderators of intervention effects. These candidate moderators included characteristics of trial methodology and implementation, intervention design and participant samples. The best-fitting random forest model identified 10 important moderators from the pool of 20 candidate moderators. Meta-regression utilizing the selected moderators found that inclusion of prescriptive advice in a BAI session significantly moderated BAI effects on alcohol use. Observed effects were also significantly moderated by several methodological characteristics of trials, including the type of comparison group used, the overall level of attrition and the strategy used to address missing data. In a meta-regression model that included all candidate moderators, fewer coefficients were found to be significant, indicating that the use of a preliminary data reduction technique to identify only important moderators for inclusion in final analyses may have yielded improved statistical power to detect moderation. Machine learning methods can be valuable tools for clarifying the influence of trial, intervention and sample characteristics on alcohol use intervention effects, in particular when numerous candidate moderators are available.

A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials.

BackgroundThe vast majority of systematic reviews are planned retrospectively, once most eligible trials have completed and reported, and are based on aggregate data that can be extracted from publications. Prior knowledge of trial results can introduce bias into both review and meta-analysis methods, and the omission of unpublished data can lead to reporting biases. We present a collaborative framework for prospective, adaptive meta-analysis (FAME) of aggregate data to provide results that are less prone to bias. Also, with FAME, we monitor how evidence from trials is accumulating, to anticipate the earliest opportunity for a potentially definitive meta-analysis.MethodologyWe developed and piloted FAME alongside 4 systematic reviews in prostate cancer, which allowed us to refine the key principles. These are to: (1) start the systematic review process early, while trials are ongoing or yet to report; (2) liaise with trial investigators to develop a detailed picture of all eligible trials; (3) prospectively assess the earliest possible timing for reliable meta-analysis based on the accumulating aggregate data; (4) develop and register (or publish) the systematic review protocol before trials produce results and seek appropriate aggregate data; (5) interpret meta-analysis results taking account of both available and unavailable data; and (6) assess the value of updating the systematic review and meta-analysis. These principles are illustrated via a hypothetical review and their application to 3 published systematic reviews.ConclusionsFAME can reduce the potential for bias, and produce more timely, thorough and reliable systematic reviews of aggregate data.