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.

An exploratory review on the empirical evaluation of the quality of reporting and analyzing labor duration.

INTRODUCTION: This exploratory review aimed to provide empirical evidence on the definitions of labor, the statistical approaches and measures reported in randomized controlled trials (RCTs) and observational studies measuring the duration of labor. METHODS: A systematic electronic literature search was conducted using different databases. An extraction form was designed and used to extract relevant data. English, French, and German studies published between 1999 and 2019 have been included. Only RCTs and observational studies analyzing labor duration (or a phase of labor duration) as a primary outcome have been included. RESULTS: Ninety-two RCTs and 126 observational studies were eligible. No definition of the onset of labor was provided in 21.7% (n = 20) of the RCTs and 23.8% (n = 30) of the observational studies. Mean was the most frequently applied measure of labor duration in the RCTs (89.1%, n = 82), and median in the observational studies (54.8%, n = 69). Most RCTs (83%, n = 76) and observational studies (70.6%, n = 89) analyzed labor duration using a bivariate method, with the t-test being the most frequently applied (45.7% and 27%, respectively). Only 10.8% (n = 10) of the RCTs and 52.4% (n = 66) of the observational studies conducted a multivariable regression: 3 (30%; out of 10) RCTs and 37 (56%; out of 66) observational studies used a time-to-event adapted model. CONCLUSION: This survey reports a lack of agreement with respect to how the onset of labor and phases of labor duration are presented. Concerning the statistical approaches, few studies used survival analysis, which is the appropriate statistical framework to analyze time-to-event data.

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.

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.

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.

Comparison of exclusion, imputation and modelling of missing binary outcome data in frequentist network meta-analysis.

BACKGROUND: Missing participant outcome data (MOD) are ubiquitous in systematic reviews with network meta-analysis (NMA) as they invade from the inclusion of clinical trials with reported participant losses. There are available strategies to address aggregate MOD, and in particular binary MOD, while considering the missing at random (MAR) assumption as a starting point. Little is known about their performance though regarding the meta-analytic parameters of a random-effects model for aggregate binary outcome data as obtained from trial-reports (i.e. the number of events and number of MOD out of the total randomised per arm). METHODS: We used four strategies to handle binary MOD under MAR and we classified these strategies to those modelling versus excluding/imputing MOD and to those accounting for versus ignoring uncertainty about MAR. We investigated the performance of these strategies in terms of core NMA estimates by performing both an empirical and simulation study using random-effects NMA based on electrical network theory. We used Bland-Altman plots to illustrate the agreement between the compared strategies, and we considered the mean bias, coverage probability and width of the confidence interval to be the frequentist measures of performance. RESULTS: Modelling MOD under MAR agreed with exclusion and imputation under MAR in terms of estimated log odds ratios and inconsistency factor, whereas accountability or not of the uncertainty regarding MOD affected intervention hierarchy and precision around the NMA estimates: strategies that ignore uncertainty about MOD led to more precise NMA estimates, and increased between-trial variance. All strategies showed good performance for low MOD (<5%), consistent evidence and low between-trial variance, whereas performance was compromised for large informative MOD (> 20%), inconsistent evidence and substantial between-trial variance, especially for strategies that ignore uncertainty due to MOD. CONCLUSIONS: The analysts should avoid applying strategies that manipulate MOD before analysis (i.e. exclusion and imputation) as they implicate the inferences negatively. Modelling MOD, on the other hand, via a pattern-mixture model to propagate the uncertainty about MAR assumption constitutes both conceptually and statistically proper strategy to address MOD in a systematic review.

Participants' outcomes gone missing within a network of interventions: Bayesian modeling strategies.

OBJECTIVES: To investigate the implications of addressing informative missing binary outcome data (MOD) on network meta-analysis (NMA) estimates while applying the missing at random (MAR) assumption under different prior structures of the missingness parameter. METHODS: In three motivating examples, we compared six different prior structures of the informative missingness odds ratio (IMOR) parameter in logarithmic scale under pattern-mixture and selection models. Then, we simulated 1000 triangle networks of two-arm trials assuming informative MOD related to interventions. We extended the Bayesian random-effects NMA model for binary outcomes and node-splitting approach to incorporate these 12 models in total. With interval plots, we illustrated the posterior distribution of log OR, common between-trial variance (τ2 ), inconsistency factor and probability of being best per intervention under each model. RESULTS: All models gave similar point estimates for all NMA estimates regardless of simulation scenario. For moderate and large MOD, intervention-specific prior structure of log IMOR led to larger posterior standard deviation of log ORs compared to trial-specific and common-within-network prior structures. Hierarchical prior structure led to slightly more precise τ2 compared to identical prior structure, particularly for moderate inconsistency and large MOD. Pattern-mixture and selection models agreed for all NMA estimates. CONCLUSIONS: Analyzing informative MOD assuming MAR with different prior structures of log IMOR affected mainly the precision of NMA estimates. Reviewers should decide in advance on the prior structure of log IMOR that best aligns with the condition and interventions investigated.

An empirical comparison of Bayesian modelling strategies for missing binary outcome data in network meta-analysis.

BACKGROUND: A number of strategies have been proposed to handle missing binary outcome data (MOD) in systematic reviews. However, none of these have been evaluated empirically in a series of published systematic reviews. METHODS: Using published systematic reviews with network meta-analysis (NMA) from a wide range of health-related fields, we evaluated comparatively the most frequently described Bayesian modelling strategies for MOD in terms of log odds ratio (log OR), between-trial variance, inconsistency factor (i.e. difference between direct and indirect estimates for a comparison), surface under the cumulative ranking (SUCRA) and rankings. We extended the Bayesian random-effects NMA model to incorporate the informative missingness odds ratio (IMOR) parameter, and applied the node-splitting approach to investigate inconsistency locally. We considered both pattern-mixture and selection models, different structures for prior distribution of log IMOR, and different scenarios for MOD. To illustrate level of agreement between different strategies and scenarios, we used Bland-Altman plots. RESULTS: Addressing MOD using extreme scenarios and ignoring the uncertainty about the scenarios led to systematically different and more precise log ORs compared to modelling MOD under the missing at random (MAR) assumption. Hierarchical structure of log IMORs led to lower between-trial variance, especially in the case of substantial MOD. Assuming common-within-network or trial-specific log IMORs yielded similar posterior results for all NMA estimates, whereas intervention-specific structure systematically inflated uncertainty around log ORs and SUCRAs. Pattern-mixture model agreed with selection model, particularly under the trial-specific structure; however, selection model systematically reduced precision around log IMORs. Overall, different strategies and scenarios mostly had good agreement in the case of low MOD. CONCLUSIONS: Addressing MOD using extreme scenarios and/or ignoring the uncertainty about the scenarios may negatively affect NMA estimates. Modelling MOD via the IMOR parameter can ensure bias-adjusted estimates and offer valuable insights into missingness mechanisms. The researcher should seek an expert opinion in order to decide on the structure of log IMOR that best aligns to the condition and interventions studied and to define a proper prior distribution for log IMOR. Our findings also apply to pairwise meta-analyses.

Association between increased antenatal vaginal pH and preterm birth rate: a systematic review.

Background Worldwide, 14.9 million infants (11%) are born preterm each year. Up to 40% of preterm births (PTBs) are associated with genital tract infections. The vaginal pH can reflect changes in the vaginal milieu and, if elevated, indicates an abnormal flora or infection. Objective The aim of the study was to investigate whether an increased antenatal vaginal pH >4.5 in pre-labour pregnant women is associated with an increased PTB rate <37 completed weeks gestation. Search strategy Key databases included SCOPUS, EMBASE, MEDLINE, PsycInfo and the Cochrane Central Register of Controlled Trials, complemented by hand search, up to January 2017. Selection criteria Primary research reporting vaginal pH assessment in pre-labour pregnant women and PTB rate. Data collection and analysis Data extraction and appraisal were carried out in a pre-defined standardised manner, applying the Newcastle-Ottawa scale (NOS) and Cochrane risk of bias tool. Analysis included calculation of risk difference (RD) and narrative synthesis. It was decided to abstain from pooling of the studies due to missing information in important moderators. Main results Of 986 identified records, 30 were included in the systematic review. The risk of bias was considered mostly high (40%) or moderate (37%). Fifteen studies permitted a calculation of RD. Of these, 14 (93%) indicated a positive association between increased antenatal vaginal pH and PTB (RD range: 0.02-0.75). Conclusion An increased antenatal vaginal pH >4.5 may be associated with a higher risk for PTB. It is recommended to conduct a randomised controlled trial (RCT) to investigate the effectiveness of antenatal pH screening to prevent PTB. Tweetable abstract Pregnant women with an increased vaginal pH >4.5 may be at higher risk to experience preterm birth.

Human Effector Memory T Helper Cells Engage with Mouse Macrophages and Cause Graft-versus-Host-Like Pathology in Skin of Humanized Mice Used in a Nonclinical Immunization Study.

Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4+ T cells in peripheral blood and lymph nodes. No weight loss, human malignancies, or systemic graft-versus-host (GVH) disease were observed. However, for one reconstitution cohort, some mice immunized with iDCpp65 showed GVH-like signs on the skin. Histopathology analyses of the inflamed skin revealed intrafollicular and perifollicular human CD4+ cells near F4/80+ mouse macrophages around hair follicles. In spleen, CD4+ cells formed large clusters surrounded by mouse macrophages. In plasma, high levels of human T helper 2-type inflammatory cytokines were detectable, which activated in vitro the STAT5 pathway of murine macrophages. Despite this inflammatory pattern, human CD8+ T cells from mice with GVH reacted against the pp65 antigen in vitro. These results uncover a dynamic cross-species interaction between human memory T cells and mouse macrophages in the skin and lymphatic tissues of humanized mice.

A systematic survey shows that reporting and handling of missing outcome data in networks of interventions is poor.

BACKGROUND: To provide empirical evidence about prevalence, reporting and handling of missing outcome data in systematic reviews with network meta-analysis and acknowledgement of their impact on the conclusions. METHODS: We conducted a systematic survey including all published systematic reviews of randomized controlled trials comparing at least three interventions from January 1, 2009 until March 31, 2017. RESULTS: We retrieved 387 systematic reviews with network meta-analysis. Description of missing outcome data was available in 63 reviews. Intention-to-treat analysis was the most prevalent method (71%), followed by missing outcome data investigated as secondary outcome (e.g., acceptability) (40%). Bias due to missing outcome data was evaluated in half the reviews with explicit judgments in 18 (10%) reviews. Only 88 reviews interpreted their results acknowledging the implications of missing outcome data and mostly using the network meta-analysis results on missing outcome data as secondary outcome. We were unable to judge the actual strategy applied to deal with missing outcome data in 65% of the reviews due to insufficient information. Six percent of network meta-analyses were re-analyzed in sensitivity analysis considering missing outcome data, while 4% explicitly justified the strategy for dealing with missing outcome data. CONCLUSIONS: The description and handling of missing outcome data as well as the acknowledgment of their implications for the conclusions from network meta-analysis are deemed underreported.

Age-related T2 relaxation times at 3 Tesla as a biomarker of infratentorial brain maturation.

PURPOSE: The purpose of this study was to examine age-related, infratentorial changes in T2 relaxation times during infancy and childhood using routine MRI data at 3 Tesla. METHODS: One hundred patients (0-199 months) without signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations. T2 maps based on our routinely acquired triple-echo turbo spin-echo (TSE) sequence were created. Based on their clinical symptoms, the children were divided into 43 controls and 57 diseased children with different clinical diseases. T2 relaxation times were measured in 15 infratentorial brain regions (medullary pyramid, ventral and dorsal pons, middle cerebellar peduncle, dentate nucleus, medial and lateral cerebellar hemisphere each on both sides, and in the cerebellar vermis) investigating age-related changes. Secondly, this study examined whether those changes in T2 values differed between healthy and diseased children. RESULTS: Age significantly reduced T2 relaxation time in all infratentorial brain regions (p < 0.05). With increasing age, the T2 relaxation times decreased continuously, faster in the first 9 months and slower thereafter. Overall, controls did not differ significantly from diseased children (p > 0.05) apart from the dentate nucleus and cerebellar hemispheres in terms of rapid decline (larger in controls) and the right dorsal pons and left pyramid in terms of slow decline (larger in diseased children). In both groups, the later slow decline was almost negligible. CONCLUSIONS: Using T2 maps, it was possible to determine age-related T2 relaxation times in the different infratentorial brain regions in this preliminary study. Between neurologically healthy controls and diseased children, no significant differences in T2 relaxation times could be found overall in the studied regions.