Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals

Kristian Thorlund1,2, Aranka Anema3, Edward Mills41Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 2The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia, Vancouver, British Columbia, Canada; 4Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, CanadaObjective: To illustrate the utility of statistical monitoring boundaries in meta-analysis, and provide a framework in which meta-analysis can be interpreted according to the adequacy of sample size. To propose a simple method for determining how many patients need to be randomized in a future trial before a meta-analysis can be deemed conclusive.Study design and setting: Prospective meta-analysis of randomized clinical trials (RCTs) that evaluated the effectiveness of isoniazid chemoprophylaxis versus placebo for preventing the incidence of tuberculosis disease among human immunodeficiency virus (HIV)-positive individuals testing purified protein derivative negative. Assessment of meta-analysis precision using trial sequential analysis (TSA) with LanDeMets monitoring boundaries. Sample size determination for a future trials to make the meta-analysis conclusive according to the thresholds set by the monitoring boundaries.Results: The meta-analysis included nine trials comprising 2,911 trial participants and yielded a relative risk of 0.74 (95% CI, 0.53–1.04, P = 0.082, I2 = 0%). To deem the meta-analysis conclusive according to the thresholds set by the monitoring boundaries, a future RCT would need to randomize 3,800 participants.Conclusion: Statistical monitoring boundaries provide a framework for interpreting meta-analysis according to the adequacy of sample size and project the required sample size for a future RCT to make a meta-analysis conclusive.Keywords: meta-analysis, trial sequential analysis (TSA), randomized clinical trials (RCTs), isoniazid chemoprophylaxis, adequacy of sample size, human immunodeficiency virus (HIV), tuberculosis, purified protein derivative negativ

Improving the interpretation of quality of life evidence in meta-analyses: the application of minimal important difference units

Systematic reviews of randomized trials that include measurements of health-related quality of life potentially provide critical information for patient and clinicians facing challenging health care decisions. When, as is most often the case, individual randomized trials use different measurement instruments for the same construct (such as physical or emotional function), authors typically report differences between intervention and control in standard deviation units (so-called "standardized mean difference" or "effect size"). This approach has statistical limitations (it is influenced by the heterogeneity of the population) and is non-intuitive for decision makers. We suggest an alternative approach: reporting results in minimal important difference units (the smallest difference patients experience as important). This approach provides a potential solution to both the statistical and interpretational problems of existing methods

Knee Arthroscopy Cohort Southern Denmark (KACS):protocol for a prospective cohort study

BACKGROUND: Meniscus surgery is a high-volume surgery carried out on 1 million patients annually in the USA. The procedure is conducted on an outpatient basis and the patients leave the hospital a few hours after surgery. A critical oversight of previous studies is their failure to account for the type of meniscal tears. Meniscus tears can be categorised as traumatic or non-traumatic. Traumatic tears (TT) are usually observed in younger, more active individuals in an otherwise ‘healthy’ meniscus and joint. Non-traumatic tears (NTT) (ie, degenerative tears) are typically observed in the middle-aged (35–55 years) and older population but the aetiology is largely unclear. Knowledge about the potential difference of the effect of arthroscopic meniscus surgery on patient symptoms between patients with traumatic and NTT is sparse. Furthermore, little is known about the natural time course of patient perceived pain, function and quality of life after meniscus surgery and factors affecting these outcomes. The aim of this prospective cohort study is to investigate the natural time course of patient-reported outcomes in patients undergoing meniscus surgery, with particular emphasis on the role of type of symptom onset. METHODS/DESIGN: This prospective cohort study enrol patients assigned for meniscus surgery. At the baseline (PRE surgery), patient characteristics are assessed using an email-based questionnaire also comprising several validated questionnaires assessing general health, knee-specific characteristics and patient's expectations of the surgery. Follow-up will be conducted at 12 and 52 weeks after meniscus surgery. The major outcomes will be differences in changes, from before to 52 weeks after surgery, in each of the five domains on the Knee injury and Osteoarthritis Outcome Score (KOOS) between patients undergoing surgery for traumatic compared with non-traumatic meniscus tears. DISSEMINATION: The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01871272

What Is the Most Bothersome Lower Urinary Tract Symptom ? Individual- and Population- level Perspectives for Both Men and Women

Peer reviewe

Scientific approaches to the deposit insurance scheme classification

У статті систематизовано існуючі підходи до класифікації систем гарантування вкладів, визначено сутність, переваги та недоліки різних видів систем гарантування вкладів. Досліджено місце вітчизняної системи гарантування вкладів у загальній класифікаціїThe article defines the existing approaches to the deposit insurance scheme classification, the essence, advantages and disadvantages of various types of deposit insurance schemes. It is also given the place of national deposit guarantee system in the general classificatio

Association of Early Interventions With Birth Outcomes and Child Linear Growth in Low-Income and Middle-Income Countries:Bayesian Network Meta-analyses of Randomized Clinical Trials

Importance:The first 1000 days of life represent a critical window for child development. Pregnancy, exclusive breastfeeding (EBF) period (0-6 months), and complementary feeding (CF) period (6-24 months) have different growth requirements, so separate considerations for intervention strategies are needed. No synthesis to date has attempted to quantify the associations of interventions under multiple domains of micronutrient and balanced energy protein and food supplements, deworming, maternal education, water sanitation, and hygiene across these 3 life periods with birth and growth outcomes. Objective: To determine the magnitude of association of interventions with birth and growth outcomes based on randomized clinical trials (RCTs) conducted in low-income and middle-income countries (LMICs) using Bayesian network meta-analyses. Data Sources: MEDLINE, Embase, and Cochrane databases were searched from their inception up to August 14, 2018. Study Selection: Included were LMIC-based RCTs of interventions provided to pregnant women, infants (0-6 months), and children (6-24 months). Data Extraction and Synthesis: Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed for each life period. Effect sizes are reported as odds ratios (ORs) and mean differences (MeanDiffs) for dichotomous and continuous outcomes, with 95% credible intervals (CrIs). This study calculated probabilities of interventions being superior to standard of care by at least a minimal clinically important difference. Main Outcomes and Measures. The study compared ORs on preterm birth and MeanDiffs on birth weight for pregnancy, length for age (LAZ) for EBF, and height for age (HAZ) for CF. Results: Among 302 061 participants in 169 randomized clinical trials, the network meta-analyses found several nutritional interventions that demonstrated greater association with improved birth and growth outcomes compared with standard of care. For instance, compared with standard of care, maternal supplements of multiple micronutrients showed reduced odds for preterm birth (OR, 0.54; 95% CrI, 0.27-0.97) and improved mean birth weight (MeanDiff, 0.08 kg; 95% CrI, 0.00-0.17 kg) but not LAZ during EBF (MeanDiff, −0.02; 95% CrI, −0.18 to 0.14). Supplementing infants and children with multiple micronutrients showed improved LAZ (MeanDiff, 0.20; 95% CrI, 0.03-0.35) and HAZ (MeanDiff, 0.14; 95% CrI, 0.02-0.25). The study found that pregnancy interventions generally had higher probabilities of a minimal clinically importance difference than the interventions for the EBF or CF in the first 1000 days of life. Conclusions and Relevance: These analyses highlight the importance of intervening early for child development, during pregnancy if possible. Results of this study suggest that there is a need to combine interventions from multiple domains and test for their effectiveness as a package

Randomised trials at the level of the individual

In global health research, short-term, small-scale clinical trials with fixed, two-arm trial designs that generally do not allow for major changes throughout the trial are the most common study design. Building on the introductory paper of this Series, this paper discusses data-driven approaches to clinical trial research across several adaptive trial designs, as well as the master protocol framework that can help to harmonise clinical trial research efforts in global health research. We provide a general framework for more efficient trial research, and we discuss the importance of considering different study designs in the planning stage with statistical simulations. We conclude this second Series paper by discussing the methodological and operational complexity of adaptive trial designs and master protocols and the current funding challenges that could limit uptake of these approaches in global health research