An investigation of the impact of using different methods for network meta-analysis: A protocol for an empirical evaluation

BACKGROUND: Network meta-analysis, a method to synthesise evidence from multiple treatments, has increased in popularity in the past decade. Two broad approaches are available to synthesise data across networks, namely, arm- and contrast-synthesis models, with a range of models that can be fitted within each. There has been recent debate about the validity of the arm-synthesis models, but to date, there has been limited empirical evaluation comparing results using the methods applied to a large number of networks. We aim to address this gap through the re-analysis of a large cohort of published networks of interventions using a range of network meta-analysis methods. METHODS: We will include a subset of networks from a database of network meta-analyses of randomised trials that have been identified and curated from the published literature. The subset of networks will include those where the primary outcome is binary, the number of events and participants are reported for each direct comparison, and there is no evidence of inconsistency in the network. We will re-analyse the networks using three contrast-synthesis methods and two arm-synthesis methods. We will compare the estimated treatment effects, their standard errors, treatment hierarchy based on the surface under the cumulative ranking (SUCRA) curve, the SUCRA value, and the between-trial heterogeneity variance across the network meta-analysis methods. We will investigate whether differences in the results are affected by network characteristics and baseline risk. DISCUSSION: The results of this study will inform whether, in practice, the choice of network meta-analysis method matters, and if it does, in what situations differences in the results between methods might arise. The results from this research might also inform future simulation studies

Congenital Hypogonadotropic Hypogonadism Due to GNRH Receptor Mutations in Three Brothers Reveal Sites Affecting Conformation and Coupling

Congenital hypogonadotropic hypogonadism (CHH) is characterized by low gonadotropins and failure to progress normally through puberty. Mutations in the gene encoding the GnRH receptor (GNRHR1) result in CHH when present as compound heterozygous or homozygous inactivating mutations. This study identifies and characterizes the properties of two novel GNRHR1 mutations in a family in which three brothers display normosmic CHH while their sister was unaffected. Molecular analysis in the proband and the affected brothers revealed two novel non-synonymous missense GNRHR1 mutations, present in a compound heterozygous state, whereas their unaffected parents possessed only one inactivating mutation, demonstrating the autosomal recessive transmission in this kindred and excluding X-linked inheritance equivocally suggested by the initial pedigree analysis. The first mutation at c.845 C>G introduces an Arg substitution for the conserved Pro 282 in transmembrane domain (TMD) 6. The Pro282Arg mutant is unable to bind radiolabeled GnRH analogue. As this conserved residue is important in receptor conformation, it is likely that the mutation perturbs the binding pocket and affects trafficking to the cell surface. The second mutation at c.968 A>G introduces a Cys substitution for Tyr 323 in the functionally crucial N/DPxxY motif in TMD 7. The Tyr323Cys mutant has an increased GnRH binding affinity but reduced receptor expression at the plasma membrane and impaired G protein-coupling. Inositol phosphate accumulation assays demonstrated absent and impaired Gαq/11 signal transduction by Pro282Arg and Tyr323Cys mutants, respectively. Pretreatment with the membrane permeant GnRHR antagonist NBI-42902, which rescues cell surface expression of many GNRHR1 mutants, significantly increased the levels of radioligand binding and intracellular signaling of the Tyr323Cys mutant but not Pro282Arg. Immunocytochemistry confirmed that both mutants are present on the cell membrane albeit at low levels. Together these molecular deficiencies of the two novel GNRHR1 mutations lead to the CHH phenotype when present as a compound heterozygote

An updated view of hypothalamic-vascular-pituitary unit function and plasticity

The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic–pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment

Recovery After Injury: An Individual Patient Data Meta-Analysis of General Health Status Using the EQ-5D

Background: General information of health-related quality of life pathways to recovery after injury are largely absent from the literature. This article describes a study which: (1) collated and synthesized individual patient data of injured persons from an earlier systematic review and (2) produced general predictions of health-related quality of life for different injury groups for up to 1 year postinjury. Methods: A systematic search of literature from January 1990 to December 2008 was completed. Researchers were approached to share their anonymous individual level data. Injuries were grouped into 39 categories based on the Eurocost injury classifications. Multilevel mixed effects models were used to produce predictions across both the five dimensions and the visual analog scale of the EQ-5D measure at 3 days, 30 days, 120 days, and 360 days postinjury. Results: Individual patient data from 10,496 injured persons (76% of known data worldwide) was retrieved. Predictions were fitted to 27 of the 39 injury categories covering a wide spectrum of injury types. Across most injuries, pain, or discomfort, usual activities and mobility were the most commonly impaired dimensions. Recovery for pain or discomfort was generally more gradual than other health dimensions. For many injury categories, a considerable proportion of people reported residual impairment at 360 days. Regardless of the anatomic location of injury, similar patterns of recovery or persistent impairment were seen for fractures and strains/sprains. Recovery patterns differed and took much longer than estimated in the Global Burden of Disease Study. Conclusions: This study has produced recovery patterns for 27 injury groups using most of the worldwide individual-level data. For many injury categories, recovery is incomplete and takes much longer than estimated. This study infers that the burden of injury is likely being underestimated

Randomised controlled trial of conservative management of postnatal urinary and faecal incontinence: six year follow-up

Objective To determine the long term effects of a conservative nurse-led intervention for postnatal urinary incontinence. Design Randomised controlled trial. Setting Community based intervention in three centres in the United Kingdom and New Zealand. Participants 747 women with urinary incontinence at three months after childbirth, of whom 516 were followed up again at 6 years (69%). Intervention Active conservative treatment (pelvic floor muscle training and bladder training) at five, seven, and nine months after delivery or standard care. Main outcome measures Urinary and faecal incontinence, performance of pelvic floor muscle training. Results Of 2632 women with urinary incontinence, 747 participated in the original trial. The significant improvements relative to controls in urinary (60% v 69%) and faecal (4% v 11%) incontinence at one year were not found at six year follow up (76% v 79% (95% confidence interval for difference in means -10.2% to 4.1%) for urinary incontinence, 12% v 13% (-6.4% to 5.1%) for faecal incontinence) irrespective of subsequent obstetric events. In the short term the intervention had motivated more women to perform pelvic floor muscle training (83% v 55%) but this fell to 50% in both groups in the long term. Both urinary and faecal incontinence increased in prevalence in both groups during the study period. Conclusions The moderate short term benefits of a brief nurse-led conservative treatment of postnatal urinary incontinence may not persist, even among women with no further deliveries. About three quarters of women with urinary incontinence three months after childbirth still have this six years later