Mixed-effects Meta-regression Models Research Articles

Influence of climate and land use on watershed anthropogenic phosphorus inputs and riverine phosphorus export dynamics: A global analysis

Many studies have found predictive relationships between riverine phosphorus (P) export and net anthropogenic P inputs (NAPI) at the watershed scale, but the global or regional extent of these relationships has not been empirically quantified. Herein, we present a data-driven global assessment of the response of riverine total P (TP) fluxes to NAPI based on 358 watersheds. NAPI exhibited high spatial heterogeneity (2–12,085 kg P km−2 yr−1) and was well correlated with riverine TP fluxes. Riverine TP export fractions of NAPI were primarily regulated by NAPI components, hydroclimate factors, and land-use as determined through a random-forest meta-analysis. In watersheds dominated by disturbed land-use (e.g., agricultural and developed lands), runoff emerged as pivotal climate-related factors influencing riverine export fractions of NAPI. In watersheds dominated by natural land-use, runoff, precipitation and temperature were identified as the most critical factors. We developed a mixed-effects meta-regression model (R2 = 0.63–0.70, RMSE = 19–78 %, n = 87–202) to examine the quantitative relationship between riverine TP fluxes and NAPI, which avoids subjectivity in selecting influencing factors and regression forms. The model estimated that legacy P contributed 14–17 % of annual riverine TP fluxes in Chinese watersheds, 25 % in North American watersheds and 11–27 % in European watersheds. Annual NAPI contributions to annual riverine TP flux were 83–86 % in China, 75 % in North America and 73–89 % in Europe. The model forecasted 52–67 %, 69–71 % and 74–77 % reductions in riverine TP fluxes across Chinese, North American, and European watersheds by 2050 under five shared socio-economic pathway scenarios compared to 2010 baseline conditions, respectively. This study provides a straightforward and reliable method for quantifying anthropogenic P input and riverine P export dynamics within an acceptable error range. It provides guidance for developing phosphorus pollution control strategies to counter potential increases in phosphorus inputs due to expected changes in climate and land use.

Rising trend and regional disparities of the global burden of disease attributable to ambient low temperature, 1990-2019: An analysis of data from the Global Burden of Disease 2019 study.

Previous studies on the effect of global warming on the global burden of disease have mainly focussed on the impact of high temperatures, thereby providing limited evidence of the effect of lower temperatures. We adopted a three-stage analysis approach using data from the Global Burden of Disease 2019 study. First, we explored the global burden of disease attributable to low temperatures, examining variations by gender, age, cause, region, and country. Second, we analysed temporal trends in low-temperature-related disease burdens from 1990 to 2019 by meta-regression. Finally, we fitted a mixed-effects meta-regression model to explore the effect modification of country-level characteristics. In 2019, low temperatures were responsible for 2.92% of global deaths and 1.03% of disability-adjusted life years (DALYs), corresponding to a death rate of 21.36 (95% uncertainty interval (UI) = 18.26, 24.73) and a DALY rate of 335 (95% UI = 280, 399) per 100 000 population. Most of the deaths (85.12%) and DALYs (94.38%) attributable to low temperatures were associated with ischaemic heart disease, stroke, and chronic obstructive pulmonary disease. In the last three decades, we observed an upward trend for the annual number of attributable deaths (P < 0.001) and a downward trend for the rates of death (P < 0.001) and DALYs (P < 0.001). The disease burden associated with low temperatures varied considerably among regions and countries, with higher burdens observed in regions with middle or high-middle socio-demographic indices, as well as countries with higher gross domestic product per capita and a larger proportion of ageing population. Our findings emphasise the significance of raising public awareness and prioritising policies to protect global population health from the adverse effects of low temperatures, even in the face of global warming. Particular efforts should be targeted towards individuals with underlying diseases (e.g. cardiovascular diseases) and vulnerable countries or regions (e.g. Central Asia and central Europe).

Magnetic Resonance Imaging, Clinical, and Biopsy Findings in Suspected Prostate Cancer

Multiple strategies integrating magnetic resonance imaging (MRI) and clinical data have been proposed to determine the need for a prostate biopsy in men with suspected clinically significant prostate cancer (csPCa) (Gleason score ≥3 + 4). However, inconsistencies across different strategies create challenges for drawing a definitive conclusion. To determine the optimal prostate biopsy decision-making strategy for avoiding unnecessary biopsies and minimizing the risk of missing csPCa by combining MRI Prostate Imaging Reporting & Data System (PI-RADS) and clinical data. PubMed, Ovid MEDLINE, Embase, Web of Science, and Cochrane Library from inception to July 1, 2022. English-language studies that evaluated men with suspected but not confirmed csPCa who underwent MRI PI-RADS followed by prostate biopsy were included. Each study had proposed a biopsy plan by combining PI-RADS and clinical data. Studies were independently assessed for eligibility for inclusion. Quality of studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies 2 tool and the Newcastle-Ottawa Scale. Mixed-effects meta-analyses and meta-regression models with multimodel inference were performed. Reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Independent risk factors of csPCa were determined by performing meta-regression between the rate of csPCa and PI-RADS and clinical parameters. Yields of different biopsy strategies were assessed by performing diagnostic meta-analysis. The analyses included 72 studies comprising 36 366 patients. Univariable meta-regression showed that PI-RADS 4 (β-coefficient [SE], 7.82 [3.85]; P = .045) and PI-RADS 5 (β-coefficient [SE], 23.18 [4.46]; P < .001) lesions, but not PI-RADS 3 lesions (β-coefficient [SE], -4.08 [3.06]; P = .19), were significantly associated with a higher risk of csPCa. When considered jointly in a multivariable model, prostate-specific antigen density (PSAD) was the only clinical variable significantly associated with csPCa (β-coefficient [SE], 15.50 [5.14]; P < .001) besides PI-RADS 5 (β-coefficient [SE], 9.19 [3.33]; P < .001). Avoiding biopsy in patients with lesions with PI-RADS category of 3 or less and PSAD less than 0.10 (vs <0.15) ng/mL2 resulted in reducing 30% (vs 48%) of unnecessary biopsies (compared with performing biopsy in all suspected patients), with an estimated sensitivity of 97% (vs 95%) and number needed to harm of 17 (vs 15). These findings suggest that in patients with suspected csPCa, patient-tailored prostate biopsy decisions based on PI-RADS and PSAD could prevent unnecessary procedures while maintaining high sensitivity.

Elimination of transmission of onchocerciasis (river blindness) with long-term ivermectin mass drug administration with or without vector control in sub-Saharan Africa: a systematic review and meta-analysis

WHO has proposed elimination of transmission of onchocerciasis (river blindness) by 2030. More than 99% of cases of onchocerciasis are in sub-Saharan Africa. Vector control and mass drug administration of ivermectin have been the main interventions for many years, with varying success. We aimed to identify factors associated with elimination of onchocerciasis transmission in sub-Saharan Africa. For this systematic review and meta-analysis we searched for published articles reporting epidemiological or entomological assessments of onchocerciasis transmission status in sub-Saharan Africa, with or without vector control. We searched MEDLINE, PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, African Index Medicus, and Google Scholar databases for all articles published from database inception to Aug 19, 2023, without language restrictions. The search terms used were "onchocerciasis" AND "ivermectin" AND "mass drug administration". The three inclusion criteria were (1) focus or foci located in Africa, (2) reporting of elimination of transmission or at least 10 years of ivermectin mass drug administration in the focus or foci, and (3) inclusion of at least one of the following assessments: microfilarial prevalence, nodule prevalence, Ov16 antibody seroprevalence, and blackfly infectivity prevalence. Epidemiological modelling studies and reviews were excluded. Four reviewers (NM, AJ, AM, and TNK) extracted data in duplicate from the full-text articles using a data extraction tool developed in Excel with columns recording the data of interest to be extracted, and a column where important comments for each study could be highlighted. We did not request any individual-level data from authors. Foci were classified as achieving elimination of transmission, being close to elimination of transmission, or with ongoing transmission. We used mixed-effects meta-regression models to identify factors associated with transmission status. This study is registered in PROSPERO, CRD42022338986. Of 1525 articles screened after the removal of duplicates, 75 provided 282 records from 238 distinct foci in 19 (70%) of the 27 onchocerciasis-endemic countries in sub-Saharan Africa. Elimination of transmission was reported in 24 (9%) records, being close to elimination of transmission in 86 (30%) records, and ongoing transmission in 172 (61%) records. I2 was 83·3% (95% CI 79·7 to 86·3). Records reporting 10 or more years of continuous mass drug administration with 80% or more therapeutic coverage of the eligible population yielded significantly higher odds of achieving elimination of transmission (log-odds 8·5 [95% CI 3·5 to 13·5]) or elimination and being close to elimination of transmission (42·4 [18·7 to 66·1]) than those with no years achieving 80% coverage or more. Reporting 15-19 years of ivermectin mass drug administration (22·7 [17·2 to 28·2]) and biannual treatment (43·3 [27·2 to 59·3]) were positively associated with elimination and being close to elimination of transmission compared with less than 15 years and no biannual mass drug administration, respectively. Having had vector control without vector elimination (-42·8 [-59·1 to -26·5]) and baseline holoendemicity (-41·97 [-60·6 to -23·2]) were associated with increased risk of ongoing transmission compared with no vector control and hypoendemicity, respectively. Blackfly disappearance due to vector control or environmental change contributed to elimination of transmission. Mass drug administration duration, frequency, and coverage; baseline endemicity; and vector elimination or disappearance are important determinants of elimination of onchocerciasis transmission in sub-Saharan Africa. Our findings underscore the importance of improving and sustaining high therapeutic coverage and increasing treatment frequency if countries are to achieve elimination of onchocerciasis transmission. The Bill & Melinda Gates Foundation and Neglected Tropical Diseases Modelling Consortium, UK Medical Research Council, and Global Health EDCTP3 Joint Undertaking. For the Swahili, French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

The impact of blinding on estimated treatment effects in randomized clinical trials on acupuncture: A meta-epidemiological study.

To evaluate the sole impact of blinding patients and outcome assessors in acupuncture randomized controlled trials (RCTs) on treatment effects while considering the type of outcome measures. We searched databases for the meta-analyses on acupuncture with both blinded and non-blinded RCTs. Mixed-effects meta-regression models estimated the average ratio of odds ratios (ROR) and differences in standardized mean differences (dSMD) for non-blinded RCTs versus blinded mixed-effects meta-regression model. The study included 96 meta-analyses (1012 trials). The average ROR for lack of patient blinding was 1.08 (95% confidence intervals 0.79-1.49) in 18 meta-analyses with binary patient-reported outcomes. The average ROR for lack of outcome assessor blinding was 0.98 (0.77-1.24) in 43 meta-analyses with binary subjective outcomes. The average dSMD was -0.38 (-0.96 to 0.20) in 10 meta-analyses with continuous patient-reported outcomes. The average dSMD was -0.13 (-0.45 to 0.18) in 25 meta-analyses with continuous subjective outcomes. The results of the subgroup analysis were consistent with the primary analysis findings. Blinding of participants and outcome assessors does not significantly influence acupuncture treatment efficacy. It underscores the practical difficulties of blinding in acupuncture RCTs and the necessity to distinguish between trials with and without successful blinding to understand treatment expectations' effects. Enhancing blinding procedures' quality and assessment in future research is crucial for improving RCTs' internal validity and reliability.

Estimated Prevalence of Depressive Disorders in Children From 2004 to 2019

Depression during childhood (ie, age <13 years) poses a major health burden. Recent changes in environmental and lifestyle factors may increase children's risk of mental health problems. This has been reported for anxiety disorders, but it is unclear whether this occurs for depressive disorders. To provide prevalence estimates for the depressive disorders (ie, major depressive disorder [MDD], dysthymia, disruptive mood dysregulation disorder [DMDD], and overall) in children, and whether they have changed over time. The MEDLINE, PsycINFO, Embase, Scopus, and Web of Science databases were searched using terms related to depressive disorders, children, and prevalence. This was supplemented by a systematic gray literature search. Studies were required to provide population prevalence estimates of depressive disorder diagnoses (according to an established taxonomy and standardized interviews) for children younger than 13 years, information about participants' year of birth, and be published in English. Data extraction was compliant with the Meta-Analysis of Observational Studies in Epidemiology guidelines. A total of 12 985 nonduplicate records were retrieved, and 154 full texts were reviewed. Data were analyzed from 2004 (the upper limit of a previous review) to May 27, 2023. Multiple proportional random-effects meta-analytic and mixed-effects meta-regression models were fit. Pooled prevalence rates of depressive disorders, prevalence rate differences between males vs females and high-income countries (HICs) vs low-and middle-income countries (LMICs), and moderating effects of time or birth cohort. A total of 41 studies were found to meet the inclusion criteria. Pooled prevalence estimates were obtained for 1.07% (95% CI, 0.62%-1.63%) for depressive disorders overall, 0.71% (95% CI, 0.48%-0.99%) for MDD, 0.30% (95% CI, 0.08%-0.62%) for dysthymia, and 1.60% (95% CI, 0.28%-3.90%) for DMDD. The meta-regressions found no significant evidence of an association with birth cohort, and prevalence rates did not differ significantly between males and females or between HICs and LMICs. There was a low risk of bias overall, except for DMDD, which was hindered by a lack of studies. In this systematic review and meta-analysis, depression in children was uncommon and did not increase substantially between 2004 and 2019. Future epidemiologic studies using standardized interviews will be necessary to determine whether this trend will continue into and beyond the COVID-19 pandemic.

A meta-analysis of GFR slope as a surrogate endpoint for kidney failure.

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min-1 per 1.73 m2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression.

The consequences of neglected confounding and interactions in mixed-effects meta-regression: An illustrative example.

Analysts seldom include interaction terms in their meta-regression model, which can introduce bias if an interaction is present. We illustrate this by reanalysing a meta-regression study in acute heart failure. Based on a total of 285 studies, the 1-year mortality rate related to acute heart failure is considered and the connection to the study-level covariates year of recruitment and average age of study participants are of interest. We show that neglecting a possibly confounding variable and an interaction term might lead to erroneous inference and conclusions. Based on our results and accompanying simulations, we recommend to include possible confounders and interaction terms, whenever they are plausible, in mixed-effects meta-regression models.

A global meta‐analysis reveals contrasting impacts of air, light, and noise pollution on pollination

In the face of biodiversity decline, understanding the impact of anthropogenic disturbances on ecosystem functions is critical for mitigation. Elevated levels of pollution are a major threat to biodiversity, yet there is no synthesis of their impact on many of the major ecosystem functions, including pollination. This ecosystem function is both particularly vulnerable as it depends on the fine-tuned interaction between plants and pollinators and hugely important as it underpins the flora of most habitats as well as food production. Here, we untangle the impact of air, light, and noise pollution on the pollination system by systematically evaluating and synthesizing the published evidence via a meta-analysis. We identified 58 peer-reviewed articles from three databases. Mixed-effects meta-regression models indicated that air pollution negatively impacts pollination. However, there was no effect of light pollution, despite previous studies that concentrated solely on pollinators suggesting a negative impact. Evidence for noise pollution was extremely limited. Unless action is taken to tackle air pollution, the capacity to support well-functioning diverse pollination systems will be compromised, with negative consequences for habitat conservation and food security.

Inter-Rater Reliability between Structured and Non-Structured Interviews Is Fair in Schizophrenia and Bipolar Disorders-A Systematic Review and Meta-Analysis.

A systematic review with meta-analysis was conducted. Publications from 2007 to 2020 comparing SDI and NSDI diagnoses in adults without neurological disorders were screened in MEDLINE, ISI Web of Science, and SCOPUS, following PROSPERO registration CRD42020187157, PRISMA guidelines, and quality assessment using QUADAS-2. From 54231 entries, 22 studies were analyzed, and 13 were included in the final meta-analysis of kappa agreement using a mixed-effects meta-regression model. A mean kappa of 0.41 (Fair agreement, 95% CI: 0.34 to 0.47) but high heterogeneity (Î2 = 92%) were calculated. Gender, mean age, NSDI setting (Inpatient vs. Outpatient; University vs. Non-university), and SDI informant (Self vs. Professional) were tested as predictors in meta-regression. Only SDI informant was relevant for the explanatory model, leaving 79% unexplained heterogeneity. Egger's test did not indicate significant bias, and QUADAS-2 resulted in "average" data quality. Most studies using SDIs do not report the original sample size, only the SDI-diagnosed patients. Kappa comparison resulted in high heterogeneity, which may reflect the influence of non-systematic bias in diagnostic processes. Although results were highly heterogeneous, we measured a fair agreement kappa between SDI and NSDI, implying clinicians might operate in scenarios not equivalent to psychiatry trials, where samples are filtered, and there may be more emphasis on maintaining reliability. The present study received no funding.

Pathological response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC): A systematic review and meta-analysis.

e20582 Background: The advantage of combining chemotherapy and immune checkpoint inhibitors (ICIs) in resectable non-small cell lung cancer (NSCLC) patients has recently been studied in clinical trial settings. We aim to systematically revise the evidence of efficacy and safety of neoadjuvant chemoimmunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Scopus, Cochrane, and ASCO meetings library. Screening was done to include clinical trials of stage I-IIIA NSCLC patients who underwent any combination of ICIs and chemotherapy. The primary outcomes were major pathological response (MPR) and pathological complete response (pCR), and the secondary outcomes were 24-month overall survival (OS) and safety measured by adverse events (AEs). A meta-analysis was conducted for intention-to-treat MPR and pCR outcomes, in addition to a mixed-effects meta-regression model to investigate the effect of PD-L1 expression, tumor mutational burden (TMB), N stage (AJCC 8th), tumor size and tumor histology on MPR and pCR. PD-L1+ patients were defined to have a tumor proportion score of more or equal to 1%. Results: We included 9 phase II clinical trials and 1 phase III trial, all consisting of 471 patients. Trials administered neoadjuvant chemotherapy agents like carboplatin (N = 6 studies), cisplatin (N = 5), nab-paclitaxel (N = 4), pemetrexed (N = 2), and others, either as a doublet- or a triplet-agent regimen. ICIs used were anti-PD-1 (N = 5), anti-PD-L1 (N = 3), or anti-CTLA-4 agents (N = 2). Meta-analysis of 447 patients from 9 trials showed a pooled MPR of 49.2% (95% CI: 34.8 to 63.7%) with high heterogeneity (I2 = 87%, p &lt; 0.01). Pooling the pCR from 10 trials including 471 patients results in an estimate of 27.5% (95% CI: 17.2 to 38.2%) with significant heterogeneity (I2 = 80%, p &lt; 0.01). Meta-regression has found a significant association between being PD-L1+ and achieving MPR (odds ratio = 3.82, 95% CI: 1.55 to 9.58). However, this effect diminished in the multiple meta-regression that included age, tumor histology, in addition to PD-L1 status. None of these factors was correlated to achieving a pCR. Investigating the effect of tumor size, T stage, N stage, or TMB on MPR or pCR was not possible due to underreported data. Three trials of 137 patients reported a 24-month OS of 84.4% (95% CI: 77.6 to 90.2%) with low heterogeneity (I2 = 11%, p = 0.33). The most prevalent grade 3/4 AEs from the neoadjuvant treatment were neutropenia in 7.2% of patients, diarrhea in 3.2%, fatigue in 3.0%, and anemia in 2.1% of patients. The commonest any-grade AEs were fatigue (43.9%), alopecia (38.4%), diarrhea (31.6%), anemia (23.8%) and neutropenia (17.0%). Conclusions: The addition of ICIs to chemotherapy in neoadjuvant settings is an effective and feasible option. Effect of tumor size, PD-L1 status and TMB on MPR and pCR should be further investigated for better selection of treatment candidates.

Accuracy of rapid point-of-care antigen-based diagnostics for SARS-CoV-2: An updated systematic review and meta-analysis with meta-regression analyzing influencing factors.

Comprehensive information about the accuracy of antigen rapid diagnostic tests (Ag-RDTs) for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is essential to guide public health decision makers in choosing the best tests and testing policies. In August 2021, we published a systematic review and meta-analysis about the accuracy of Ag-RDTs. We now update this work and analyze the factors influencing test sensitivity in further detail. We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched preprint and peer-reviewed databases for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 until August 31, 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity with reverse transcription polymerase chain reaction (RT-PCR) testing as a reference. To evaluate factors influencing test sensitivity, we performed 3 different analyses using multivariable mixed-effects meta-regression models. We included 194 studies with 221,878 Ag-RDTs performed. Overall, the pooled estimates of Ag-RDT sensitivity and specificity were 72.0% (95% confidence interval [CI] 69.8 to 74.2) and 98.9% (95% CI 98.6 to 99.1). When manufacturer instructions were followed, sensitivity increased to 76.3% (95% CI 73.7 to 78.7). Sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values (97.9% [95% CI 96.9 to 98.9] and 90.6% [95% CI 88.3 to 93.0] for Ct-values <20 and <25, compared to 54.4% [95% CI 47.3 to 61.5] and 18.7% [95% CI 13.9 to 23.4] for Ct-values ≥25 and ≥30) and was estimated to increase by 2.9 percentage points (95% CI 1.7 to 4.0) for every unit decrease in mean Ct-value when adjusting for testing procedure and patients' symptom status. Concordantly, we found the mean Ct-value to be lower for true positive (22.2 [95% CI 21.5 to 22.8]) compared to false negative (30.4 [95% CI 29.7 to 31.1]) results. Testing in the first week from symptom onset resulted in substantially higher sensitivity (81.9% [95% CI 77.7 to 85.5]) compared to testing after 1 week (51.8%, 95% CI 41.5 to 61.9). Similarly, sensitivity was higher in symptomatic (76.2% [95% CI 73.3 to 78.9]) compared to asymptomatic (56.8% [95% CI 50.9 to 62.4]) persons. However, both effects were mainly driven by the Ct-value of the sample. With regards to sample type, highest sensitivity was found for nasopharyngeal (NP) and combined NP/oropharyngeal samples (70.8% [95% CI 68.3 to 73.2]), as well as in anterior nasal/mid-turbinate samples (77.3% [95% CI 73.0 to 81.0]). Our analysis was limited by the included studies' heterogeneity in viral load assessment and sample origination. Ag-RDTs detect most of the individuals infected with SARS-CoV-2, and almost all (>90%) when high viral loads are present. With viral load, as estimated by Ct-value, being the most influential factor on their sensitivity, they are especially useful to detect persons with high viral load who are most likely to transmit the virus. To further quantify the effects of other factors influencing test sensitivity, standardization of clinical accuracy studies and access to patient level Ct-values and duration of symptoms are needed.

Location-scale models for meta-analysis.

Heterogeneity is commonplace in meta-analysis. When heterogeneity is found, researchers often aim to identify predictors that account for at least part of such heterogeneity by using mixed-effects meta-regression models. Another potentially relevant goal is to focus on the amount of heterogeneity as a function of one or more predictors, but this cannot be examined with standard random- and mixed-effects models, which assume a constant (i.e., homoscedastic) value for the heterogeneity variance component across studies. In this paper, we describe a location-scale model for meta-analysis as an extension of the standard random- and mixed-effects models that not only allows an examination of whether predictors are related to the size of the outcomes (i.e., their location), but also the amount of heterogeneity (i.e., their scale). We present estimation methods for such a location-scale model through maximum and restricted maximum likelihood approaches, as well as methods for inference and suggestions for visualization. We also provide an implementation via the metafor package for R that makes this model readily available to researchers. Location-scale models can provide a useful tool to researchers interested in heterogeneity in meta-analysis, with the potential to enhance the scope of research questions in the field of evidence synthesis.

VP14: Long-Term Explantations and Complications of Autologous Heterotopic Bone Graft Versus Alloplastic Cranioplasties: A Systematic Review and Metaanalysis

INTRODUCTION: When immediate autologous bone replacement is not possible following cranioplasty, autologous reconstruction may occur via delayed replacement with banked or grafted fresh heterotopic autologous bone, or alloplastic implants composed of polyetheretherketone (PEEK), polymethylmethacrylate (PMMA), or titanium. In this work, we performed a systematic review and meta-analysis evaluating long-term cranioplasty outcomes of fresh, heterotopic autologous bone versus alloplastic materials. MATERIALS AND METHODS: A systematic review was conducted on PubMed for studies published between March 1971 and December 2020. Inclusion criteria consisted of a mean follow-up ≥12 months. Exclusion criteria included reporting craniosynostosis, and cranial vault remodeling. Extracted variables included patient demographics, operative details, and proportions of explantations and complications. We performed a random effects meta-analysis model and a mixed effects meta-regression model to compare pooled proportions of explantations and complications for each material. RESULTS: Thirty articles met the inclusion criteria totaling 109 autologous and 1130 alloplastic patients, averaging a 31.49±20.70 month follow-up, 37.33±13.50 years of age, and 61.26±33.25 cm2 defect size. Compared to bone, there were greater proportions of explantations for PMMA (Point Estimate (PE)=1.56, 95%C.I.=0.24–2.88, p=0.02) and of complications for PMMA (PE=2.04, 95%C.I.=0.62–3.47, p<0.01) and titanium (PE=1.64, 95%C.I.=0.25–3.03, p=0.02). When follow-up was included as an independent variable (PE=-0.02, 95%C.I=-0.04–-0.01, p=0.01), PEEK exhibited greater proportions of complications compared to bone (PE=1.78, 95%C.I.=0.27–3.29, p=0.02). CONCLUSION: Our findings suggest that compared to bone, PMMA and titanium exhibited greater proportions of explantations meanwhile all included alloplastic materials exhibited greater proportions of complications, decreasing by 2% with every month of follow-up.

A Meta-analysis of the Uncanny Valley's Independent and Dependent Variables

The uncanny valley (UV) effect is a negative affective reaction to human-looking artificial entities. It hinders comfortable, trust-based interactions with android robots and virtual characters. Despite extensive research, a consensus has not formed on its theoretical basis or methodologies. We conducted a meta-analysis to assess operationalizations of human likeness (independent variable) and the UV effect (dependent variable). Of 468 studies, 72 met the inclusion criteria. These studies employed 10 different stimulus creation techniques, 39 affect measures, and 14 indirect measures. Based on 247 effect sizes, a three-level meta-analysis model revealed the UV effect had a large effect size, Hedges’ g = 1.01 [0.80, 1.22]. A mixed-effects meta-regression model with creation technique as the moderator variable revealed face distortion produced the largest effect size, g = 1.46 [0.69, 2.24], followed by distinct entities, g = 1.20 [1.02, 1.38], realism render, g = 0.99 [0.62, 1.36], and morphing, g = 0.94 [0.64, 1.24]. Affective indices producing the largest effects were threatening, likable, aesthetics, familiarity , and eeriness , and indirect measures were dislike frequency, categorization reaction time, like frequency, avoidance , and viewing duration . This meta-analysis—the first on the UV effect—provides a methodological foundation and design principles for future research.

Human norovirus contamination in water sources: A systematic review and meta-analysis

The human norovirus (HNoV), on a global scale, is the prevailing cause of contagious viral gastroenteritis outbreaks, with more than 200 000 deaths annually. This study aimed at assessing specific prevalence of HNoV pollution in different water sources and their roles in the dissemination of HNoV, with a view to refocus water sources and sewage management options for policy making towards public health safety. In this regard, we conducted a systematic review and meta-analysis (SR/MA) of the prevalence of HNoV in water sources. We searched PubMed, Google Scholar, Scopus and Web of Science for studies on HNoV prevalence in water sources without temporal restriction, till January 30, 2021. We conducted a random-effects meta-analysis of the HNoV prevalence and stratified the study by water type, continent, gross national income (GNI) group and genogroup. Further, a mixed-effects meta-regression model was performed for sensitivity analysis. The literature search identified 61 studies on water source-based HNoV (WsHNoV) prevalence. The pooled WsHNoV prevalence was 31.7% (95%CI: 25.1–38.5) but varied according to water sources types; river water showing the highest estimate at 43.5% (95%CI: 33.9–53.4), followed by estuarine water (30.6%, 95%CI: 12.5–52.2), composite water (27.9%, 95%CI: 13.5–44.9), marine water (25.9%, 95%CI: 10.0–45.6), groundwater (19.7%, 95%CI: 9.4–32.3) and lake water (2.2%, 95%CI: 0–25.8). Further, the findings indicated the highest WsHNoV prevalence in Africa as 55.9% (95% CI: 28.2–81.9), followed by Asia (31.6%, 95% CI: 22.3–41.6), Europe (29.8%, 95% CI: 17.9–43.2), North America (27.7%, 95% CI: 11.2–47.6) and South America (27.1%, 95%CI: 0.09–49.4). The WsHNoV prevalence stratified by GNI group was 40.6% (95%CI: 27.9–53.9) in middle-income countries and 28.7% (95%CI: 21.7–36.1) in high-income countries respectively. The prevalence of GI, GII and GI & GII genogroup in natural water was 16.4% (95%CI: 12.0–21.3), 20.6% (95%CI: 15.7–25.8) and 12.8% (95%CI: 6.9–20.6) respectively. Evidently, prevalence of the HNoV genogroup in water sources mirrors the pattern of HNoV gastroenteritis and GII genogroup dominance worldwide. In conclusion, public health efforts against waterborne diseases should prioritize water resource/sewage management options and policies towards ardent water sources pollution prevention.

The Relationship Between Endoscopic and Clinical Recurrence in Postoperative Crohn's Disease: A Systematic Review and Meta-analysis.

We aimed to quantify the magnitude of the association between endoscopic recurrence and clinical recurrence [symptom relapse] in patients with postoperative Crohn's disease. Databases were searched to October 2, 2020, for randomised controlled trials [RCTs] and cohort studies of adult patients with Crohn's disease with ileocolonic resection and anastomosis. Summary effect estimates for the association between clinical recurrence and endoscopic recurrence were quantified by risk ratios [RR] and 95% confidence intervals [95% CI]. Mixed-effects meta-regression evaluated the role of confounders. Spearman correlation coefficients were calculated to assess the relationship between these outcomes as endpoints in RCTs. An exploratory mixed-effects meta-regression model with the logit of the rate of clinical recurrence as the outcome and the rate of endoscopic recurrence as a predictor was also evaluated. In all, 37 studies [N = 4053] were included. For eight RCTs with available data, the RR for clinical recurrence for patients who experienced endoscopic recurrence was 10.77 [95% CI 4.08 to 28.40; GRADE moderate certainty evidence]; the corresponding estimate from 11 cohort studies was 21.33 [95% CI 9.55 to 47.66; GRADE low certainty evidence]. A single cohort study showed a linear relationship between Rutgeerts score and clinical recurrence risk. There was a strong correlation between endoscopic recurrence and clinical recurrence treatment effect estimates as trial outcomes [weighted Spearman correlation coefficient 0.51]. The associations between endoscopic recurrence and subsequent clinical recurrence lend support to the choice of endoscopic recurrence to monitor postoperative disease activity and as a primary endpoint in clinical trials of postoperative Crohn's disease.

Routine Capsular Closure With Hip Arthroscopic Surgery Results in Superior Outcomes: A Systematic Review and Meta-analysis

Background: In hip arthroscopic surgery, capsulotomy is performed to improve visualization and allow instrumentation of the joint. Traditionally, the defect has been left unrepaired; however, increasing evidence suggests that this may contribute to persistent pain and iatrogenic capsular instability. Nevertheless, the clinical benefit of performing routine capsular repair remains controversial. Purpose/Hypothesis: We conducted a systematic review and meta-analysis to investigate the effects of routine capsular closure on patient-reported outcomes (PROs), hypothesizing that superior PROs would be observed with routine capsular closure. Study Design: Meta-analysis and systematic review; Level of evidence, 4. Methods: A systematic review and meta-analysis was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The terms “hip,”“arthroscopy,”“capsule,”“capsular,”“repair,” and “closure” were used to query Ovid MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), CINAHL (Cumulative Index to Nursing and Allied Health Literature), SPORTDiscus, and PubMed. Articles with PROs stratified by capsular management were included. Multivariate mixed-effects metaregression models were implemented with study-level random-effects and fixed-effects moderators for capsular closure versus no repair and after controlling for surgical indication and preoperative PROs. The effect of repair on both the postoperative score and the change in scores was evaluated via the Harris Hip Score (HHS)/modified HHS (mHHS), Hip Outcome Score (HOS)–Activities of Daily Living (ADL), and HOS–Sport Specific Subscale (SSS), with a supplemental analysis of additional outcomes. Results: Of 432 initial articles, 36 were eligible for analysis, with results for 5132 hip arthroscopic procedures. The capsule was repaired in 3427 arthroscopic procedures and unrepaired in 1705. Capsular repair was associated with significantly higher postoperative HHS/mHHS (2.011; SE, 0.743 [95% CI, 0.554-3.467]; P = .007), HOS-ADL (3.635; SE, 0.873 [95% CI, 1.923-5.346]; P < .001), and HOS-SSS (4.137; SE, 1.205 [95% CI, 1.775-6.499]; P < .001) scores as well as significantly superior improvement on the HHS/mHHS (2.571; SE, 0.878 [95% CI, 0.849-4.292]; P = .003), HOS-ADL (3.315; SE, 1.131 [95% CI, 1.099-5.531]; P = .003), and HOS-SSS (3.605; SE, 1.689 [95% CI, 0.295-6.915]; P = .033). Conclusion: This meta-analysis is the largest to date evaluating the effect of capsular closure on PROs and demonstrates significantly higher mean postoperative scores and significantly superior improvement with repair, while controlling for the effects of preoperative score and surgical indication. The true magnitude of the benefit of capsular repair may be clarified by large prospective randomized studies using PRO measures specifically targeted and validated for hip arthroscopic surgery/preservation.

Systematic Review and Meta-Analysis: Clinical, Endoscopic, Histological and Safety Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them. MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level. In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9-13%), 19% [95% CI 15-23%] and 15% [95% CI 11-19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12-25%] and 20% [95% CI 15-25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates. Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design.

Parental education and inequalities in child mortality: a global systematic review and meta-analysis

SummaryBackgroundThe educational attainment of parents, particularly mothers, has been associated with lower levels of child mortality, yet there is no consensus on the magnitude of this relationship globally. We aimed to estimate the total reductions in under-5 mortality that are associated with increased maternal and paternal education, during distinct age intervals.MethodsThis study is a comprehensive global systematic review and meta-analysis of all existing studies of the effects of parental education on neonatal, infant, and under-5 child mortality, combined with primary analyses of Demographic and Health Survey (DHS) data. The literature search of seven databases (CINAHL, Embase, MEDLINE, PsycINFO, PubMed, Scopus, and Web of Science) was done between Jan 23 and Feb 8, 2019, and updated on Jan 7, 2021, with no language or publication date restrictions. Teams of independent reviewers assessed each record for its inclusion of individual-level data on parental education and child mortality and excluded articles on the basis of study design and availability of relevant statistics. Full-text screening was done in 15 languages. Data extracted from these studies were combined with primary microdata from the DHS for meta-analyses relating maternal or paternal education with mortality at six age intervals: 0–27 days, 1–11 months, 1–4 years, 0–4 years, 0–11 months, and 1 month to 4 years. Novel mixed-effects meta-regression models were implemented to address heterogeneity in referent and exposure measures among the studies and to adjust for study-level covariates (wealth or income, partner's years of schooling, and sex of the child). This study was registered with PROSPERO (CRD42020141731).FindingsThe systematic review returned 5339 unique records, yielding 186 included studies after exclusions. DHS data were compiled from 114 unique surveys, capturing 3 112 474 livebirths. Data extracted from the systematic review were synthesized together with primary DHS data, for meta-analysis on a total of 300 studies from 92 countries. Both increased maternal and paternal education showed a dose–response relationship linked to reduced under-5 mortality, with maternal education emerging as a stronger predictor. We observed a reduction in under-5 mortality of 31·0% (95% CI 29·0–32·6) for children born to mothers with 12 years of education (ie, completed secondary education) and 17·3% (15·0–18·8) for children born to fathers with 12 years of education, compared with those born to a parent with no education. We also showed that a single additional year of schooling was, on average, associated with a reduction in under-5 mortality of 3·04% (2·82–3·23) for maternal education and 1·57% (1·35–1·72) for paternal education. The association between higher parental education and lower child mortality was significant for both parents at all ages studied and was largest after the first month of life. The meta-analysis framework incorporated uncertainty associated with each individual effect size into the model fitting process, in an effort to decrease the risk of bias introduced by study design and quality.InterpretationTo our knowledge, this study is the first effort to systematically quantify the transgenerational importance of education for child survival at the global level. The results showed that lower maternal and paternal education are both risk factors for child mortality, even after controlling for other markers of family socioeconomic status. This study provides robust evidence for universal quality education as a mechanism to achieve the Sustainable Development Goal target 3.2 of reducing neonatal and child mortality.FundingResearch Council of Norway, Bill & Melinda Gates Foundation, and Rockefeller Foundation-Boston University Commission on Social Determinants, Data, and Decision Making (3-D Commission).