Language bias in orthodontic systematic reviews: A meta-epidemiological study.

BACKGROUND: Orthodontic systematic reviews (SRs) include studies published mostly in English than non-English languages. Including only English studies in SRs may result in a language bias. This meta-epidemiological study aimed to evaluate the language bias impact on orthodontic SRs. DATA SOURCE: SRs published in high-impact orthodontic journals between 2017 and 2021 were retrieved through an electronic search of PubMed in June 2022. Additionally, Cochrane oral health group was searched for orthodontic systematic reviews published in the same period. DATA COLLECTION AND ANALYSIS: Study selection and data extraction were performed by two authors. Multivariable logistic regression was implemented to explore the association of including non-English studies with the SRs characteristics. For the meta-epidemiological analysis, one meta-analysis from each SRs with at least three trials, including one non-English trial was extracted. The average difference in SMD was obtained using a random-effects meta-analysis. RESULTS: 174 SRs were included in this study. Almost one-quarter (n = 45/174, 26%) of these SRs included at least one non-English study. The association between SRs characteristics and including non-English studies was not statistically significant except for the restriction on language: the odds of including non-English studies reduced by 89% in SRs with a language restriction (OR: 0.11, 95%CI: 0.01 0.55, P< 0.01). Out of the sample, only fourteen meta-analyses were included in the meta-epidemiological analysis. The meta-epidemiological analysis revealed that non-English studies tended to overestimate the summary SMD by approximately 0.30, but this was not statistically significant when random-effects model was employed due to substantial statistical heterogeneity (ΔSMD = -0.29, 95%CI: -0.63 to 0.05, P = 0.37). As such, the overestimation of meta-analysis results by including non-English studies was statistically non-significant. CONCLUSION: Language bias has non-negligible impact on the results of orthodontic SRs. Orthodontic systematic reviews should abstain from language restrictions and use sensitivity analysis to assess the impact of language on the conclusions, as non-English studies may have a lower quality.

Low awareness of the transitivity assumption in complex networks of interventions: a systematic survey from 721 network meta-analyses.

BACKGROUND: The transitivity assumption is the cornerstone of network meta-analysis (NMA). Violating transitivity compromises the credibility of the indirect estimates and, by extent, the estimated treatment effects of the comparisons in the network. The present study offers comprehensive empirical evidence on the completeness of reporting and evaluating transitivity in systematic reviews with multiple interventions. METHODS: We screened the datasets of two previous empirical studies, resulting in 361 systematic reviews with NMA published between January 2011 and April 2015. We updated our evidence base with an additional 360 systematic reviews with NMA published between 2016 and 2021, employing a pragmatic approach. We devised assessment criteria for reporting and evaluating transitivity using relevant methodological literature and compared their reporting frequency before and after the PRISMA-NMA statement. RESULTS: Systematic reviews published after PRISMA-NMA were more likely to provide a protocol (odds ratio (OR): 3.94, 95% CI: 2.79-5.64), pre-plan the transitivity evaluation (OR: 3.01, 95% CI: 1.54-6.23), and report the evaluation and results (OR: 2.10, 95% CI: 1.55-2.86) than those before PRISMA-NMA. However, systematic reviews after PRISMA-NMA were less likely to define transitivity (OR: 0.57, 95% CI: 0.42-0.79) and discuss the implications of transitivity (OR: 0.48, 95% CI: 0.27-0.85) than those published before PRISMA-NMA. Most systematic reviews evaluated transitivity statistically than conceptually (40% versus 12% before PRISMA-NMA, and 54% versus 11% after PRISMA-NMA), with consistency evaluation being the most preferred (34% before versus 47% after PRISMA-NMA). One in five reviews inferred the plausibility of the transitivity (22% before versus 18% after PRISMA-NMA), followed by 11% of reviews that found it difficult to judge transitivity due to insufficient data. In justifying their conclusions, reviews considered mostly the comparability of the trials (24% before versus 30% after PRISMA-NMA), followed by the consistency evaluation (23% before versus 16% after PRISMA-NMA). CONCLUSIONS: Overall, there has been a slight improvement in reporting and evaluating transitivity since releasing PRISMA-NMA, particularly in items related to the systematic review report. Nevertheless, there has been limited attention to pre-planning the transitivity evaluation and low awareness of the conceptual evaluation methods that align with the nature of the assumption.

Convolutional Neural Network for Fully Automated Cerebellar Volumetry in Children in Comparison to Manual Segmentation and Developmental Trajectory of Cerebellar Volumes.

The purpose of this study was to develop a fully automated and reliable volumetry of the cerebellum of children during infancy and childhood using deep learning algorithms in comparison to manual segmentation. In addition, the clinical usefulness of measuring the cerebellar volume is shown. One hundred patients (0 to 16.3 years old) without infratentorial signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations. Based on a routinely acquired 3D T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence, the cerebella were manually segmented using ITK-SNAP. The data set of all 100 cases was divided into four splits (four-fold cross-validation) to train the network (NN) to delineate the boundaries of the cerebellum. First, the accuracy of the newly created neural network was compared with the manual segmentation. Secondly, age-related volume changes were investigated. Our trained NN achieved an excellent Spearman correlation coefficient of 0.99, a Dice Coefficient of 95.0 ± 2.1%, and an intersection over union (IoU) of 90.6 ± 3.8%. Cerebellar volume increased continuously with age, showing an exponentially rapid growth within the first year of life. Using a convolutional neural network, it was possible to achieve reliable, fully automated cerebellar volume measurements in childhood and infancy, even when based on a relatively small cohort. In this preliminary study, age-dependent cerebellar volume changes could be acquired.

Is there a difference among different bonded retainers in regard to survival rate?

Design A retrospective study.Cohort selection Inclusion criteria included: participants of any age who had completed their fixed orthodontic treatment on both arches and were treated by the same orthodontist in their private practice; had bonded retainers for five years, which were placed immediately after the orthodontic treatment in both arches; had one of three types of bonded retainers (0.026 × 0.010 inch Bond-A-Braid, 0.038 × 0.016 inch Ortho-FlexTech and Reliance Retainium Superior Brand Lingual Retainer Wire); had a final overbite of 2-4 mm after the completion of orthodontic treatment. Subjects who got their retainers changed, repaired or removed before five years, and syndromic patients, were excluded from the study.Data analysis The participants who agreed to contribute to the study and came for the final clinical examination were assessed for the retention status and the periodontal/gingival indies. Retention and retainer status: unwanted tooth movements and time and type of retainer failure. Periodontal/gingival indies: maximum pocket depth (PD) from the lingual side for the retained teeth and bleeding on probing (BOP). The authors performed a series of analyses to compare the orthodontic retainers regarding several outcomes and demographic variables. Briefly, the authors compared the orthodontic retainers concerning: i) age and treatment duration using analysis of variance (since the data were found to be normally distributed based on the Kolmogorov-Smirnov test); ii) demographic variables and BOP using several Chi-square tests; iii) PD via the Kruskal-Wallis test; and iv) survival rate through a Cox regression model alongside log-rank test.Results In total, 118 patients were included in this study, of which, 90 were women and 28 were men, with an average age of 22.34 ± 6.44 years. There was no statistically significant difference in the survival rate between the three types of retainers or between men and women. Likewise, there was no statistically significant difference in survival rate between the different age groups for the maxilla and mandible. Different maximum and minimum failure rates were observed between teeth in the maxilla and the mandible in the three retainers' group.Conclusions No difference was found between the three types of bonded retainers in regard to the survival rate and periodontal indices.

A Revised Framework to Evaluate the Consistency Assumption Globally in a Network of Interventions.

BACKGROUND: The unrelated mean effects (UME) model has been proposed for evaluating the consistency assumption globally in the network of interventions. However, the UME model does not accommodate multiarm trials properly and omits comparisons between nonbaseline interventions in the multiarm trials not investigated in 2-arm trials. METHODS: We proposed a refinement of the UME model that tackles the limitations mentioned above. We also accompanied the scatterplots on the posterior mean deviance contributions of the trial arms under the network meta-analysis (NMA) and UME models with Bland-Altman plots to detect outlying trials contributing to poor model fit. We applied the refined and original UME models to 2 networks with multiarm trials. RESULTS: The original UME model omitted more than 20% of the observed comparisons in both networks. The thorough inspection of the individual data points' deviance contribution using complementary plots in conjunction with the measures of model fit and the estimated between-trial variance indicated that the refined and original UME models revealed possible inconsistency in both examples. CONCLUSIONS: The refined UME model allows proper accommodation of the multiarm trials and visualization of all observed evidence in complex networks of interventions. Furthermore, considering several complementary plots to investigate deviance helps draw informed conclusions on the possibility of global inconsistency in the network. HIGHLIGHTS: We have refined the unrelated mean effects (UME) model to incorporate multiarm trials properly and to estimate all observed comparisons in complex networks of interventions.Forest plots with posterior summaries of all observed comparisons under the network meta-analysis and refined UME model can uncover the consequences of potential inconsistency in the network.Using complementary plots to investigate the individual data points' deviance contribution in conjunction with model fit measures and estimated heterogeneity aid in detecting possible inconsistency.

How robust are findings of pairwise and network meta-analysis in the presence of missing participant outcome data?

BACKGROUND: To investigate the prevalence of robust conclusions in systematic reviews addressing missing (participant) outcome data via a novel framework of sensitivity analyses and examine the agreement with the current sensitivity analysis standards. METHODS: We performed an empirical study on systematic reviews with two or more interventions. Pairwise meta-analyses (PMA) and network meta-analyses (NMA) were identified from empirical studies on the reporting and handling of missing outcome data in systematic reviews. PMAs with at least three studies and NMAs with at least three interventions on one primary outcome were considered eligible. We applied Bayesian methods to obtain the summary effect estimates whilst modelling missing outcome data under the missing-at-random assumption and different assumptions about the missingness mechanism in the compared interventions. The odds ratio in the logarithmic scale was considered for the binary outcomes and the standardised mean difference for the continuous outcomes. We calculated the proportion of primary analyses with robust and frail conclusions, quantified by our proposed metric, the robustness index (RI), and current sensitivity analysis standards. Cohen's kappa statistic was used to measure the agreement between the conclusions derived by the RI and the current sensitivity analysis standards. RESULTS: One hundred eight PMAs and 34 NMAs were considered. When studies with a substantial number of missing outcome data dominated the analyses, the number of frail conclusions increased. The RI indicated that 59% of the analyses failed to demonstrate robustness compared to 39% when the current sensitivity analysis standards were employed. Comparing the RI with the current sensitivity analysis standards revealed that two in five analyses yielded contradictory conclusions concerning the robustness of the primary analysis results. CONCLUSIONS: Compared with the current sensitivity analysis standards, the RI offers an explicit definition of similar results and does not unduly rely on statistical significance. Hence, it may safeguard against possible spurious conclusions regarding the robustness of the primary analysis results.

Induced dendritic cells co-expressing GM-CSF/IFN-α/tWT1 priming T and B cells and automated manufacturing to boost GvL.

Acute myeloid leukemia (AML) patients with minimal residual disease and receiving allogeneic hematopoietic stem cell transplantation (HCT) have poor survival. Adoptive administration of dendritic cells (DCs) presenting the Wilms tumor protein 1 (WT1) leukemia-associated antigen can potentially stimulate de novo T and B cell development to harness the graft-versus-leukemia (GvL) effect after HCT. We established a simple and fast genetic modification of monocytes for simultaneous lentiviral expression of a truncated WT1 antigen (tWT1), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon (IFN)-α, promoting their self-differentiation into potent "induced DCs" (iDCtWT1). A tricistronic integrase-defective lentiviral vector produced under good manufacturing practice (GMP)-like conditions was validated. Transduction of CD14+ monocytes isolated from peripheral blood, cord blood, and leukapheresis material effectively induced their self-differentiation. CD34+ cell-transplanted Nod.Rag.Gamma (NRG)- and Nod.Scid.Gamma (NSG) mice expressing human leukocyte antigen (HLA)-A∗0201 (NSG-A2)-immunodeficient mice were immunized with autologous iDCtWT1. Both humanized mouse models showed improved development and maturation of human T and B cells in the absence of adverse effects. Toward clinical use, manufacturing of iDCtWT1 was up scaled and streamlined using the automated CliniMACS Prodigy system. Proof-of-concept clinical-scale runs were feasible, and the 38-h process enabled standardized production and high recovery of a cryopreserved cell product with the expected identity characteristics. These results advocate for clinical trials testing iDCtWT1 to boost GvL and eradicate leukemia.

Quantifying the robustness of primary analysis results: A case study on missing outcome data in pairwise and network meta-analysis.

Conducting sensitivity analyses is an integral part of the systematic review process to explore the robustness of results derived from the primary analysis. When the primary analysis results can be sensitive to assumptions concerning a model's parameters (e.g., missingness mechanism to be missing at random), sensitivity analyses become necessary. However, what can be concluded from sensitivity analyses is not always clear. For instance, in a pairwise meta-analysis (PMA) and network meta-analysis (NMA), conducting sensitivity analyses usually boils down to examining how 'similar' the estimated treatment effects are from different re-analyses to the primary analysis or placing undue emphasis on the statistical significance. To establish objective decision rules regarding the robustness of the primary analysis results, we propose an intuitive index, which uses the whole distribution of the estimated treatment effects under the primary and alternative re-analyses. This novel index is compared to an objective threshold to infer the presence or lack of robustness. In the case of missing outcome data, we additionally propose a graph that contrasts the primary analysis results to those of alternative scenarios about the missingness mechanism in the compared arms. When robustness is questioned according to the proposed index, the suggested graph can demystify the scenarios responsible for producing inconsistent results to the primary analysis. The proposed decision framework is immediately applicable to a broad set of sensitivity analyses in PMA and NMA. We illustrate our framework in the context of missing outcome data in both PMA and NMA using published systematic reviews.

Root coverage stability: A systematic overview of controlled clinical trials with at least 5 years of follow-up.

OBJECTIVES: To systematically assess the long-term outcome (≥5 years) of root coverage procedures reported in controlled clinical trials. MATERIAL AND METHODS: Literature search was performed according to the PRISMA guidelines with the following eligibility criteria: (a) English or German language; (b) controlled (CT) or randomised controlled clinical trials (RCT); (c) root coverage procedure with ≥5 years follow-up; and (d) clinical treatment effect size and/or patient-related outcome measures (PROMs) reported. RESULTS: Four CT and 14 RCT with a follow-up of 5-20 years fulfilled the eligibility criteria; sample size per study ranged from 8 to 70 patients contributing with 18-149 sites. Coronally advanced flap (CAF) and CAF + connective tissue graft (CTG) were the prevalent treatments (i.e., in 24 and 38% of the groups, respectively), while other flap designs and adjuncts (i.e., enamel matrix derivative, bone graft, collagen membrane) were represented only once. For single Miller class I/II gingival recessions (GR), CAF + CTG appeared advantageous compared to other techniques, and provided low residual recession depths (i.e., ≤0.5 mm), and complete root coverage in ≥2/3 of the patients; similar tendency was observed for multiple GR. No data on Miller class III/IV GR is available. No meta-analysis was feasible due to lack of similarity in the clinical and methodological characteristics across the trials and observed comparisons of interventions. CONCLUSIONS: CAF + CTG appears to be the 'gold standard' technique for the treatment of single and multiple Miller class I/II GR also in regard to long-term (i.e., ≥5 years of follow-up) treatment outcomes. There is little information regarding the performance, on the long-term, of other techniques and adjuncts.

Continuous(ly) missing outcome data in network meta-analysis: A one-stage pattern-mixture model approach.

Appropriate handling of aggregate missing outcome data is necessary to minimise bias in the conclusions of systematic reviews. The two-stage pattern-mixture model has been already proposed to address aggregate missing continuous outcome data. While this approach is more proper compared with the exclusion of missing continuous outcome data and simple imputation methods, it does not offer flexible modelling of missing continuous outcome data to investigate their implications on the conclusions thoroughly. Therefore, we propose a one-stage pattern-mixture model approach under the Bayesian framework to address missing continuous outcome data in a network of interventions and gain knowledge about the missingness process in different trials and interventions. We extend the hierarchical network meta-analysis model for one aggregate continuous outcome to incorporate a missingness parameter that measures the departure from the missing at random assumption. We consider various effect size estimates for continuous data, and two informative missingness parameters, the informative missingness difference of means and the informative missingness ratio of means. We incorporate our prior belief about the missingness parameters while allowing for several possibilities of prior structures to account for the fact that the missingness process may differ in the network. The method is exemplified in two networks from published reviews comprising a different amount of missing continuous outcome data.

Pattern-mixture model in network meta-analysis of binary missing outcome data: one-stage or two-stage approach?

BACKGROUND: Trials with binary outcomes can be synthesised using within-trial exact likelihood or approximate normal likelihood in one-stage or two-stage approaches, respectively. The performance of the one-stage and the two-stage approaches has been documented extensively in the literature. However, little is known about how these approaches behave in the presence of missing outcome data (MOD), which are ubiquitous in clinical trials. In this work, we compare the one-stage versus two-stage approach via a pattern-mixture model in the network meta-analysis using Bayesian methods to handle MOD appropriately. METHODS: We used 29 published networks to empirically compare the two approaches concerning the relative treatment effects of several competing interventions and the between-trial variance (τ2), while considering the extent and level of balance of MOD in the included trials. We additionally conducted a simulation study to compare the competing approaches regarding the bias and width of the 95% credible interval of the (summary) log odds ratios (OR) and τ2 in the presence of moderate and large MOD. RESULTS: The empirical study did not reveal any systematic bias between the compared approaches regarding the log OR, but showed systematically larger uncertainty around the log OR under the one-stage approach for networks with at least one small trial or low event risk and moderate MOD. For these networks, the simulation study revealed that the bias in log OR for comparisons with the reference intervention in the network was relatively higher in the two-stage approach. Contrariwise, the bias in log OR for the remaining comparisons was relatively higher in the one-stage approach. Overall, bias increased for large MOD. For these networks, the empirical results revealed slightly higher τ2 estimates under the one-stage approach irrespective of the extent of MOD. The one-stage approach also led to less precise log OR and τ2 when compared with the two-stage approach for large MOD. CONCLUSIONS: Due to considerable bias in the log ORs overall, especially for large MOD, none of the competing approaches was superior. Until a more competent model is developed, the researchers may prefer the one-stage approach to handle MOD, while acknowledging its limitations.

Medium- and long-term clinical benefits of periodontal regenerative/reconstructive procedures in intrabony defects: Systematic review and network meta-analysis of randomized controlled clinical studies.

BACKGROUND: Systematic reviews have established the short-term improvements of periodontal regenerative/reconstructive procedures compared to conventional surgical treatment in intrabony defects. However, a hierarchy of periodontal regenerative/reconstructive procedures regarding the medium- to long-term results of treatment does not exist. AIM: To systematically assess the literature to answer the focused question "In periodontitis patients with intrabony defects, what are the medium- and long-term benefits of periodontal regenerative/reconstructive procedures compared with open flap debridement (OFD), in terms of clinical and/or radiographic outcome parameters and tooth retention?". MATERIAL & METHODS: Randomized controlled clinical trials (RCTs), reporting on clinical and/or radiographic outcome parameters of periodontal regenerative/reconstructive procedures ≥3 years post-operatively, were systematically assessed. Clinical [residual probing pocket depth (PD) and clinical attachment level (CAL) gain, tooth loss] and radiographic [residual defect depth (RDD), bone gain (RBL)] outcome parameters were assessed. Descriptive statistics were calculated, and Bayesian random-effects network meta-analyses (NMA) were performed where possible. RESULTS: Thirty RCTs, presenting data 3 to 20 years after treatment with grafting, GTR, EMD, as monotherapies, combinations thereof, and/or adjunctive use of blood-derived growth factor constructs or with OFD only, were included. NMA based on 21 RCTs showed that OFD was clearly the least efficacious treatment; regenerative/reconstructive treatments resulted in significantly shallower residual PD in 4 out 8 comparisons [range of mean differences (MD): -2.37 to -0.60 mm] and larger CAL gain in 6 out 8 comparisons (range of MD: 1.26 to 2.66 mm), and combination approaches appeared as the most efficacious. Tooth loss after regenerative/reconstructive treatment was less frequent (0.4%) compared to OFD (2.8%), but the evidence was sparse. There were only sparse radiographic data not allowing any relevant comparisons. CONCLUSION: Periodontal regenerative/reconstructive therapy in intrabony defects results, in general, in shallower residual PD and larger CAL gain compared with OFD, translating in high rates of tooth survival, on a medium (3-5 years) to long-term basis (5-20 years). Combination approaches appear, in general, more efficacious compared to monotherapy in terms of shallower residual PD and larger CAL gain. A clear hierarchy could, however, not be established due to limited evidence.