Methodological Quality and Reporting of Generalized Linear Mixed Models in Clinical Medicine (2000–2012): A Systematic Review

Background

Modeling count and binary data collected in hierarchical designs have increased the use of Generalized Linear Mixed Models (GLMMs) in medicine. This article presents a systematic review of the application and quality of results and information reported from GLMMs in the field of clinical medicine.

Methods

A search using the Web of Science database was performed for published original articles in medical journals from 2000 to 2012. The search strategy included the topic “generalized linear mixed models”,“hierarchical generalized linear models”, “multilevel generalized linear model” and as a research domain we refined by science technology. Papers reporting methodological considerations without application, and those that were not involved in clinical medicine or written in English were excluded.

Results

A total of 443 articles were detected, with an increase over time in the number of articles. In total, 108 articles fit the inclusion criteria. Of these, 54.6% were declared to be longitudinal studies, whereas 58.3% and 26.9% were defined as repeated measurements and multilevel design, respectively. Twenty-two articles belonged to environmental and occupational public health, 10 articles to clinical neurology, 8 to oncology, and 7 to infectious diseases and pediatrics. The distribution of the response variable was reported in 88% of the articles, predominantly Binomial (n = 64) or Poisson (n = 22). Most of the useful information about GLMMs was not reported in most cases. Variance estimates of random effects were described in only 8 articles (9.2%). The model validation, the method of covariate selection and the method of goodness of fit were only reported in 8.0%, 36.8% and 14.9% of the articles, respectively.

Conclusions

During recent years, the use of GLMMs in medical literature has increased to take into account the correlation of data when modeling qualitative data or counts. According to the current recommendations, the quality of reporting has room for improvement regarding the characteristics of the analysis, estimation method, validation, and selection of the model.     

Modeling of Novel Diagnostic Strategies for Active Tuberculosis – A Systematic Review: Current Practices and Recommendations

Introduction

The field of diagnostics for active tuberculosis (TB) is rapidly developing. TB diagnostic modeling can help to inform policy makers and support complicated decisions on diagnostic strategy, with important budgetary implications. Demand for TB diagnostic modeling is likely to increase, and an evaluation of current practice is important. We aimed to systematically review all studies employing mathematical modeling to evaluate cost-effectiveness or epidemiological impact of novel diagnostic strategies for active TB.

Methods

Pubmed, personal libraries and reference lists were searched to identify eligible papers. We extracted data on a wide variety of model structure, parameter choices, sensitivity analyses and study conclusions, which were discussed during a meeting of content experts.

Results & Discussion

From 5619 records a total of 36 papers were included in the analysis. Sixteen papers included population impact/transmission modeling, 5 were health systems models, and 24 included estimates of cost-effectiveness. Transmission and health systems models included specific structure to explore the importance of the diagnostic pathway (n = 4), key determinants of diagnostic delay (n = 5), operational context (n = 5), and the pre-diagnostic infectious period (n = 1). The majority of models implemented sensitivity analysis, although only 18 studies described multi-way sensitivity analysis of more than 2 parameters simultaneously. Among the models used to make cost-effectiveness estimates, most frequent diagnostic assays studied included Xpert MTB/RIF (n = 7), and alternative nucleic acid amplification tests (NAATs) (n = 4). Most (n = 16) of the cost-effectiveness models compared new assays to an existing baseline and generated an incremental cost-effectiveness ratio (ICER).

Conclusion

Although models have addressed a small number of important issues, many decisions regarding implementation of TB diagnostics are being made without the full benefits of insight from mathematical models. Further models are needed that address a wider array of diagnostic and epidemiological settings, that explore the inherent uncertainty of models and that include additional epidemiological data on transmission implications of false-negative diagnosis and the pre-diagnostic period.     

Outfoxing a Rash: Clinical Example of Human–Wildlife Interaction

Increasing human–wildlife contact can manifest in a variety of clinical conditions that may be overlooked by both human health and veterinary professionals. We report on an outbreak of scabies infection in a community, affecting both animals and humans, and representing the effects of an emerging infectious disease in a wildlife population. These cases underscore the potential importance of animal sentinel events for human, animal, and ecosystem health. The treatment given to the human cases of infection ranged from aggressive therapy to watchful waiting, with similar outcomes. There is a need for further collaborative, evidence-based research by human and veterinary health professionals into the optimal treatment and prevention of infections resulting from cross-species transmission.     

Clinical Significance of Tumor Necrosis Factor-α Inhibitors in the Treatment of Sciatica: A Systematic Review and Meta-Analysis

Background and Objective

Currently, no satisfactory treatment is available for sciatica caused by herniated discs and/or spinal stenosis. The objective of this study is to assess the value of tumor necrosis factor (TNF)-α inhibitors in the treatment of sciatica.

Methods

Without language restrictions, we searched PubMed, OVID, EMBASE, the Web of Science, the Clinical Trials Registers, the Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. We then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria.

Results

Nine prospective randomized controlled trials (RCTs) and two before-after controlled trials involving 531 patients met our inclusion criteria and were included in this study. Our systematic assessment and meta-analysis demonstrated that in terms of the natural course of the disease, compared with the control condition, TNF-α inhibitors neither significantly relieved lower back and leg pain (both p>0.05) nor enhanced the proportion of patients who felt overall satisfaction (global perceived effect (satisfaction)) or were able to return to work (return to work) (combined endpoint; p>0.05) at the short-term, medium-term and long-term follow-ups. In addition, compared with the control condition, TNF-α inhibitors could reduce the risk ratio (RR) of discectomy or radicular block (combined endpoint; RR = 0.51, 95% CI 0.26 to 1.00, p = 0.049) at medium-term follow-up, but did not decrease RR at the short-term (RR = 0.64, 95% CI 0.17 to 2.40, p = 0.508) and long-term follow-ups (RR = 0.64, 95% CI 0.40 to 1.03, p = 0.065).

Conclusion

The currently available evidence demonstrated that other than reducing the RR of discectomy or radicular block (combined endpoint) at medium-term follow-up, TNF-α inhibitors showed limited clinical value in the treatment of sciatica caused by herniated discs and/or spinal stenosis.     

Melatonin as a Neuroprotective Agent in the Rodent Models of Parkinson’s Disease: Is it All Set to Irrefutable Clinical Translation?

Parkinson’s disease (PD), a neurodegenerative disorder, is characterized by the selective degeneration of the nigrostriatal dopaminergic neurons, continuing or permanent deficiency of dopamine, accretion of an abnormal form of alpha synuclein in the adjacent neurons, and dysregulation of ubiquitin proteasomal system, mitochondrial metabolism, permeability and integrity, and cellular apoptosis resulting in rigidity, bradykinesia, resting tremor, and postural instability. Melatonin, an indoleamine produced almost in all the organisms, has anti-inflammatory, anti-apoptotic, and anti-oxidant nature. Experimental studies employing 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), methamphetamine, rotenone, and maneb and paraquat models have shown an enormous potential of melatonin in amelioration of the symptomatic features of PD. Although a few reviews published previously have described the multifaceted efficacy of melatonin against MPTP and 6-OHDA rodent models, due to development and validation of the newer models as well as the extensive studies on the usage of melatonin in entrenched PD models, it is worthwhile to bring up to date note on the usage of melatonin as a neuroprotective agent in PD. This article presents an update on the usage and applications of melatonin in PD models along with incongruous observations. The impending implications in the clinics, success, limitations, and future prospective have also been discussed in this article.     

Development and Evaluation of ‘Briefing Notes’ as a Novel Knowledge Translation Tool to Aid the Implementation of Sex/Gender Analysis in Systematic Reviews: A Pilot Study

Background

There is increasing recognition of sex/gender differences in health and the importance of identifying differential effects of interventions for men and women. Yet, to whom the research evidence does or does not apply, with regard to sex/gender, is often insufficiently answered. This is also true for systematic reviews which synthesize results of primary studies. A lack of analysis and reporting of evidence on sex/gender raises concerns about the applicability of systematic reviews. To bridge this gap, this pilot study aimed to translate knowledge about sex/gender analysis (SGA) into a user-friendly ‘briefing note’ format and evaluate its potential in aiding the implementation of SGA in systematic reviews.

Methods

Our Sex/Gender Methods Group used an interactive process to translate knowledge about sex/gender into briefing notes, a concise communication tool used by policy and decision makers. The briefing notes were developed in collaboration with three Cochrane Collaboration review groups (HIV/AIDS, Hypertension, and Musculoskeletal) who were also the target knowledge users of the briefing notes. Briefing note development was informed by existing systematic review checklists, literature on sex/gender, in-person and virtual meetings, and consultation with topic experts. Finally, we held a workshop for potential users to evaluate the notes.

Results

Each briefing note provides tailored guidance on considering sex/gender to reviewers who are planning or conducting systematic reviews and includes the rationale for considering sex/gender, with examples specific to each review group’s focus. Review authors found that the briefing notes provided welcome guidance on implementing SGA that was clear and concise, but also identified conceptual and implementation challenges.

Conclusions

Sex/gender briefing notes are a promising knowledge translation tool. By encouraging sex/gender analysis and equity considerations in systematic reviews, the briefing notes can assist systematic reviewers in ensuring the applicability of research evidence, with the goal of improved health outcomes for diverse populations.     

The Effects of Kinesiotape Applied to the Lateral Aspect of the Ankle: Relevance to Ankle Sprains – A Systematic Review

Objective

To identify, evaluate and synthesise evidence on the effect of kinesiotape applied to the lateral aspect of the ankle, through a systematic review of quantitative studies.

Data Sources

A search for quantitative studies was undertaken using key terms of “kinesiotape” and “ankle” in seven electronic databases, using the maximum date ranges. Databases included: the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Medline, Physiotherapy Evidence Database, Scopus, SPORTDiscus and Web of Science.

Study Selection

Database hits were evaluated against explicit inclusion criteria. From 107 database hits, 8 quantitative studies were included.

Data Extraction

Two independent reviewers appraised the methodological rigour of the studies using the McMaster Critical Review Form for Quantitative Studies. Data were extracted on participant characteristics, kinesiotape parameters, comparison interventions, outcome measures and findings.

Data Syntheses

Most studies (n=7) had good to very good methodological rigour. Meta-analysis was not possible due to heterogeneity in participants, interventions and outcome measures. No adverse events were reported. Kinesiotape may produce different effects in healthy and injured ankles. In healthy ankles, kinesiotape may increase postural control, whereas in injured ankles it may improve proprioception, plantarflexor endurance and the performance of activities. These trends were identified from a small body of evidence including 276 participants.

Conclusions

It is recommended that kinesiotape may be used in clinical practice to prevent lateral ankle injuries (through its effects on postural control) and manage lateral ankle injuries due to its positive effects on proprioception, muscle endurance and activity performance. It appears that kinesiotape may not provide sufficient mechanical support to improve postural control in unstable ankles. Adverse events associated with kinseiotape are unlikely.     

Camping in a Different Tree: Results of Molecular Systematic Studies of Bats Using DNA–DNA Hybridization

We examined taxa from 13 of the 17 chiropteran families, using single-copy DNA hybridization. Five taxa that either represented points of controversy in systematics or were members of problematic families were included in the experiment. The resulting data were used to build phylogenetic trees of 14 and 19 taxa, and by combining this study's data with those from two previous studies, a supertree of 36 taxa was constructed. The trees based on the three different matrices are compared and contrasted, and a phylogenetic hypothesis supporting the association of the rhinolophoid and the pteropodid groups of bats is presented. On the basis of this study, we conclude that the phylogenetically correct placement of the family Nycteridae is in a clade that does not include their putative relatives, the Rhinolophoidea. Our results suggest that the Emballonuridae, while a monophyletic group, are well embedded within the Yangochiroptera, and do not comprise the sister taxon to all other microbats. This study supports earlier DNA-hybridization results with respect to the placement of Mystacinidae within the Noctilionoidea, replicating those earlier findings. Finally, we determine that Miniopterus may well warrant recognition as a family distinct from the Vespertilionidae in which it is usually placed.     

Italian Association of Clinical Endocrinologists Statement–Replacement Therapy for Primary Hypothyroidism: A Brief Guide for Clinical Practice

Objective: Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (LT4) is an established safe and effective treatment for hypothyroidism, but some issues remain unsettled.Methods: The Italian Association of Clinical Endocrinologists appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for hypothyroidism replacement therapy. The American Association of Clinical Endocrinologists' protocol for standardized production of clinical practice guidelines was followed.Results: LT4 is the first choice in replacement therapy. Thyroid-stimulating hormone (TSH) should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient well-being, and adherence to treatment should be addressed. In patients with unstable serum TSH, a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered LT4 absorption or who do not allow sufficient time before or after meals and LT4 replacement. Replacement therapy with LT4 and L-triiodothyronine (LT3) combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after co-existent nonthyroid problems have been excluded or optimally managed. LT3 should be administered in small (LT4:LT3 ratio, 10:1 to 20:1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy.Conclusion: LT4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH, and improvement of quality of life. In selected cases, the use of liquid LT4 formulations or combined LT4/LT3 treatment may be considered to improve adherence to treatment or patient well-being.Abbreviations:AACE = American Association of Clinical EndocrinologistsFT3 = free triiodothyronineFT4 = free thyroxineLT3 = levotriiodothyronineLT4 = levothyroxineMeSH = medicine medical subject headingsQoL = quality of lifeTSH = thyroid-stimulating hormone     

Solid-State Li–Metal Batteries: Challenges and Horizons of Oxide and Sulfide Solid Electrolytes and Their Interfaces

The introduction of new, safe, and reliable solid-electrolyte chemistries and technologies can potentially overcome the challenges facing their liquid counterparts while widening the breadth of possible applications. Through tech-historic evolution and rationally analyzing the transition from liquid-based Li-ion batteries (LIBs) to all-solid-state Li-metal batteries (ASSLBs), a roadmap for the development of a successful oxide and sulfide-based ASSLB focusing on interfacial challenges is introduced, while accounting for five parameters: energy density, power density, longterm stability, processing, and safety. First taking a strategic approach, this review dismantles the ASSLB into its three major components and discusses the most promising solid electrolytes and their most advantageous pairing options with oxide cathode materials and the Li metal anode. A thorough analysis of the chemical, electrochemical, and mechanical properties of the two most promising and investigated classes of inorganic solid electrolytes, namely oxides and sulfides, is presented. Next, the overriding challenges associated with the pairing of the solid electrolyte with oxide-based cathodes and a Li-metal anode, leading to limited performance for solid-state batteries are extensively addressed and possible strategies to mitigate these issues are presented. Finally, future perspectives, guidelines, and selective interface engineering strategies toward the resolution of these challenges are analyzed and discussed.     

Obtaining Self-Samples to Diagnose Curable Sexually Transmitted Infections: A Systematic Review of Patients’ Experiences

Background

Routine screening is key to sexually transmitted infection (STI) prevention and control. Previous studies suggest that clinic-based screening programmes capture only a small proportion of people with STIs. Self-sampling using non- or minimally invasive techniques may be beneficial for those reluctant to actively engage with conventional sampling methods. We systematically reviewed studies of patients’ experiences of obtaining self-samples to diagnose curable STIs.

Methods

We conducted an electronic search of MEDLINE, EMBASE, CINAHL, PsychINFO, BNI, and Cochrane Database of Systematic Reviews to identify relevant articles published in English between January 1980 and March 2014. Studies were included if participants self-sampled for the diagnosis of a curable STI and had specifically sought participants’ opinions of their experience, acceptability, preferences, or willingness to self-sample.

Results

The initial search yielded 558 references. Of these, 45 studies met the inclusion criteria. Thirty-six studies assessed patients’ acceptability and experiences of self-sampling. Pooled results from these studies shows that self-sampling is a highly acceptable method with 85% of patients reporting the method to be well received and acceptable. Twenty-eight studies reported on ease of self-sampling; the majority of patients (88%) in these studies found self-sampling an “easy” procedure. Self-sampling was favoured compared to clinician sampling, and home sampling was preferred to clinic-based sampling. Females and older participants were more accepting of self-sampling. Only a small minority of participants (13%) reported pain during self-sampling. Participants were willing to undergo self-sampling and recommend others. Privacy and safety were the most common concerns.

Conclusion

Self-sampling for diagnostic testing is well accepted with the majority having a positive experience and willingness to use again. Standardization of self-sampling procedures and rigorous validation of outcome measurement will lead to better comparability across studies. Future studies need to conduct rigorous economic evaluations of self-sampling to inform policy development for the management of STI.     

Recruitment of brown fat and conversion of white into brown adipocytes: Strategies to fight the metabolic complications of obesity?

The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a matter of debate, and the molecular mechanisms underlying brown adipocyte development remained largely unknown. In 2009, several studies brought direct evidence for functional brown adipose tissue in adults. New factors involved in brown fat cell differentiation have been identified. Moreover, work on the origin of fat cells took an unexpected path with the recognition of different populations of brown fat cell precursors according to the anatomical location of the fat depots: a precursor common to skeletal muscle cells and brown adipocytes from brown fat depots, and a progenitor cell common to white adipocytes and brown adipocytes that appear in certain conditions in white fat depots. There is also mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications.     

Epidemiology of Dengue Disease in Malaysia (2000–2012): A Systematic Literature Review

A literature survey and analysis was conducted to describe the epidemiology of dengue disease in Malaysia between 2000 and 2012. Published literature was searched for epidemiological studies of dengue disease, using specific search strategies for each electronic database; 237 relevant data sources were identified, 28 of which fulfilled the inclusion criteria. The epidemiology of dengue disease in Malaysia was characterized by a non-linear increase in the number of reported cases from 7,103 in 2000 to 46,171 in 2010, and a shift in the age range predominance from children toward adults. The overall increase in dengue disease was accompanied by a rise in the number, but not the proportion, of severe cases. The dominant circulating dengue virus serotypes changed continually over the decade and differed between states. Several gaps in epidemiological knowledge were identified; in particular, studies of regional differences, age-stratified seroprevalence, and hospital admissions.

Protocol registration

PROSPERO #CRD42012002293

Author summary

Dengue disease is a tropical and subtropical mosquito-borne viral illness, and is a major health concern in Malaysia. We conducted this literature analysis and review to describe the epidemiology of dengue disease in Malaysia between 2000 and 2012, to determine the impact of dengue disease on the Malaysian population, and to identify future research priorities. We used well-defined methods to search and identify relevant research, and data were selected according to predetermined inclusion criteria. This long-term review highlights the changing epidemiology of dengue fever in Malaysia. Although the overall incidence has stabilized in recent years, dengue disease remains a public health burden. Our review demonstrates an increased incidence of all forms of dengue disease and a predominantly adult age distribution. Changes in circulating dengue virus serotypes may have implications for the incidence and severity of dengue disease. Increasing levels of rainfall, humidity, temperature, and urbanization have been identified as risk factors for dengue disease outbreak. We believe that the recent improvements to the surveillance system in Malaysia should, if pursued over the next few years, greatly improve our understanding of the burden of dengue fever and enable us to monitor the impact of disease control measures in the future.     

Funding Infectious Disease Research: A Systematic Analysis of UK Research Investments by Funders 1997–2010

Background

Research investments are essential to address the burden of disease, however allocation of limited resources is poorly documented. We systematically reviewed the investments awarded by funding organisations to UK institutions and their global partners for infectious disease research.

Methodology/Principal Findings

Public and philanthropic investments for the period 1997 to 2010 were included. We categorised studies by infectious disease, cross-cutting theme, and by research and development value chain, reflecting the type of science. We identified 6165 funded studies, with a total research investment of UK £2.6 billion. Public organisations provided £1.4 billion (54.0%) of investments compared with £1.1 billion (42.4%) by philanthropic organisations. Global health studies represented an investment of £928 million (35.7%). The Wellcome Trust was the leading investor with £688 million (26.5%), closely followed by the UK Medical Research Council (MRC) with £673 million (25.9%). Funding over time was volatile, ranging from ∼£40 million to ∼£160 million per year for philanthropic organisations and ∼£30 million to ∼£230 million for public funders.

Conclusions/Significance

Infectious disease research funding requires global coordination and strategic long-term vision. Our analysis demonstrates the diversity and inconsistent patterns in investment, with volatility in annual funding amounts and limited investment for product development and clinical trials.     

Epidemiology of Dengue Disease in the Philippines (2000–2011): A Systematic Literature Review

This literature analysis describes the available dengue epidemiology data in the Philippines between 2000 and 2011. Of 253 relevant data sources identified, 34, including additional epidemiology data provided by the National Epidemiology Center, Department of Health, Philippines, were reviewed. There were 14 publications in peer reviewed journals, and 17 surveillance reports/sources, which provided variable information from the passive reporting system and show broad trends in dengue incidence, including age group predominance and disease severity. The peer reviewed studies focused on clinical severity of cases, some revealed data on circulating serotypes and genotypes and on the seroepidemiology of dengue including incidence rates for infection and apparent disease. Gaps in the data were identified, and include the absence incidence rates stratified by age, dengue serotype and genotype distribution, disease severity data, sex distribution data, and seroprevalence data.

Protocol registration

PROSPERO CRD42012002292     

Epidemiological Trends of Dengue Disease in Thailand (2000–2011): A Systematic Literature Review

A literature survey and analysis was conducted to describe the epidemiology of dengue disease in Thailand reported between 2000 and 2011. The literature search identified 610 relevant sources, 40 of which fulfilled the inclusion criteria defined in the review protocol. Peaks in the number of cases occurred during the review period in 2001, 2002, 2008 and 2010. A shift in age group predominance towards older ages continued through the review period. Disease incidence and deaths remained highest in children aged ≤15 years and case fatality rates were highest in young children. Heterogeneous geographical patterns were observed with higher incidence rates reported in the Southern region and serotype distribution varied in time and place. Gaps identified in epidemiological knowledge regarding dengue disease in Thailand provide several avenues for future research, in particular studies of seroprevalence.

Protocol registration

PROSPERO CRD42012002170