Cost-effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies.

BACKGROUND: We sought to determine the cost-effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies in Canada. STUDY DESIGN AND METHODS: We developed two probabilistic state-transition (Markov) microsimulation models to compare fetal genotyping followed by targeted management versus usual care (i.e., universal Rh immunoglobulin [RhIG] prophylaxis in nonalloimmunized RhD-negative pregnancies, or universal intensive monitoring in alloimmunized pregnancies). The reference case considered a healthcare payer perspective and a 10-year time horizon. Sensitivity analysis examined assumptions related to test cost, paternal screening, subsequent pregnancies, other alloantibodies (e.g., K, Rh c/C/E), societal perspective, and lifetime horizon. RESULTS: Fetal genotyping in nonalloimmunized pregnancies (at per-sample test cost of C$247/US$311) was associated with a slightly higher probability of maternal alloimmunization (22 vs. 21 per 10,000) and a reduced number of RhIG injections (1.427 vs. 1.795) than usual care. It was more expensive (C$154/US$194, 95% Credible Interval [CrI]: C$139/US$175-C$169/US$213) and had little impact on QALYs (0.0007, 95%CrI: -0.01-0.01). These results were sensitive to the test cost (threshold achieved at C$88/US$111), and inclusion of paternal screening. Fetal genotyping in alloimmunized pregnancies (at test cost of C$328/US$413) was less expensive (-C$6280/US$7903, 95% CrI: -C$6325/US$7959 to -C$6229/US$7838) and more effective (0.19 QALYs, 95% CrI 0.17-0.20) than usual care. These cost savings remained robust in sensitivity analyses. DISCUSSION: Noninvasive fetal RhD genotyping saves resources and represents good value for the management of alloimmunized pregnancies. If the cost of genotyping is substantially decreased, the targeted intervention can become a viable option for nonalloimmunized pregnancies.

Noninvasive Fetal RhD Blood Group Genotyping: A Systematic Review of Economic Evaluations.

OBJECTIVE: Noninvasive fetal rhesus D (RhD) blood group genotyping may prevent unnecessary use of anti-D immunoglobulin (RhIG) in non-alloimmunized RhD-negative pregnancies and can guide management of alloimmunized pregnancies. We conducted a systematic review of the economic literature to determine the cost-effectiveness of this intervention over usual care. DATA SOURCES: Systematic literature searches of bibliographic databases (Ovid MEDLINE, Embase, and Cochrane) until February 26, 2019, and auto-alerts until October 30, 2020, and of grey literature sources were performed to retrieve all English-language studies. STUDY SELECTION: We included studies done in serologically confirmed non-alloimmunized or alloimmunized RhD-negative pregnancies, comparing costs and effectiveness of the intervention versus usual care. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data from the eligible studies and assessed their methodological quality (risk of bias) using the Quality of Health Economic Studies (QHES) and Drummond tools. We narratively synthesized findings. Our review included 8 economic studies that evaluated non-invasive fetal RhD genotyping followed by targeted RhIG prophylaxis in non-alloimmunized pregnancies. Five studies further considered a subsequent alloimmunized pregnancy. The cost-effectiveness of the intervention versus usual care (e.g., universal RhIG or prophylaxis conditional on results of paternal testing) for non-alloiummunized pregnancies was inconsistent. Two studies indicated greater benefits and lower costs for the intervention, and another 2 suggested a trade-off. In 4 studies, the intervention was less effective and costlier than alternatives. Three studies were determined to be of high quality by both tools. Two of these studies favoured the intervention, and one assessed benefits in quality-adjusted life-years. No study clearly examined the cost-effectiveness of repetitive use of fetal genotyping in multiple non-alloimmunized or alloimmunized pregnancies. The cost of genotyping was the most influential parameter. CONCLUSION: The cost-effectiveness of noninvasive fetal RhD genotyping for non-alloimmunized pregnancies varies between studies. Potential savings from targeted management of alloimmunized pregnancies requires further research.

Cost-Effectiveness of Magnetic Resonance-Guided Focused Ultrasound for Essential Tremor.

BACKGROUND: Radiofrequency thalamotomy and deep brain stimulation are current treatments for moderate to severe medication-refractory essential tremor. However, they are invasive and thus carry risks. Magnetic resonance-guided focused ultrasound is a new, less invasive surgical option. The objective of the present study was to determine the cost-effectiveness of magnetic resonance-guided focused ultrasound compared with standard treatments in Canada. METHODS: We conducted a cost-utility analysis using a Markov cohort model. We compared magnetic resonance-guided focused ultrasound with no surgery in people ineligible for invasive neurosurgery and with radiofrequency thalamotomy and deep brain stimulation in people eligible for invasive neurosurgery. In the reference case analysis, we used a 5-year time horizon and a public payer perspective and discounted costs and benefits at 1.5% per year. RESULTS: Compared with no surgery in people ineligible for invasive neurosurgery, magnetic resonance-guided focused ultrasound cost $21,438 more but yielded 0.47 additional quality-adjusted life years, producing an incremental cost-effectiveness ratio of $45,817 per quality-adjusted life year gained. In people eligible for invasive neurosurgery, magnetic resonance-guided focused ultrasound was slightly less effective but much less expensive compared with the current standard of care, deep brain stimulation. The results were sensitive to assumptions regarding the time horizon, cost of magnetic resonance-guided focused ultrasound, and probability of recurrence. CONCLUSIONS: In people ineligible for invasive neurosurgery, the incremental cost-effectiveness ratio of magnetic resonance-guided focused ultrasound versus no surgery is comparable to many other tests and treatments that are widely adopted in high-income countries. In people eligible for invasive neurosurgery, magnetic resonance-guided focused ultrasound is also a reasonable option. © 2018 International Parkinson and Movement Disorder Society.

A Non-inferiority Framework for Cost-Effectiveness Analysis.

BACKGROUND: Traditional decision rules have limitations when a new technology is less effective and less costly than a comparator. We propose a new probabilistic decision framework to examine non-inferiority in effectiveness and net monetary benefit (NMB) simultaneously. We illustrate this framework using the example of repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) for treatment-resistant depression. METHODS: We modeled the quality-adjusted life-years (QALYs) associated with the new intervention (rTMS), an active control (ECT), and a placebo control, and we estimated the fraction of effectiveness preserved by the new intervention through probabilistic sensitivity analysis (PSA). We then assessed the probability of cost-effectiveness using a traditional cost-effectiveness acceptability curve (CEAC) and our new decision-making framework. In our new framework, we considered the new intervention cost-effective in each simulation of the PSA if it preserved at least 75 percent of the effectiveness of the active control (thus demonstrating non-inferiority) and had a positive NMB at a given willingness-to-pay threshold (WTP). RESULTS: rTMS was less effective (i.e., associated with fewer QALYs) and less costly than ECT. The traditional CEAC approach showed that the probabilities of rTMS being cost-effective were 100 percent, 39 percent, and 14 percent at WTPs of $0, $50,000, and $100,000 per QALY gained, respectively. In the new decision framework, the probabilities of rTMS being cost-effective were reduced to 23 percent, 21 percent, and 13 percent at WTPs of $0, $50,000, and $100,000 per QALY, respectively. CONCLUSIONS: This new framework provides a different perspective for decision making with considerations of both non-inferiority and WTP thresholds.

Osteoporotic fractures and obesity affect frailty progression: a longitudinal analysis of the Canadian multicentre osteoporosis study.

BACKGROUND: Despite knowing better how to screen older adults, understanding how frailty progression might be modified is unclear. We explored effects of modifiable and non-modifiable factors on changes in frailty in community-dwelling adults aged 50+ years who participated in the Canadian Multicentre Osteoporosis Study (CaMos). METHODS: Rates of change in frailty over 10 years were examined using the 30-item CaMos Frailty Index (CFI). Incident and prevalent low-trauma fractures were categorized by fracture site into hip, clinical vertebral and non-hip-non-vertebral fractures. Multivariable generalized estimating equation models accounted for the time of frailty assessment (baseline, 5 and 10 years), sex, age, body mass index (BMI, kg/m2), physical activity, bone mineral density, antiresorptive therapy, health-related quality of life (HRQL), cognitive status, and other factors for frailty or fractures. Multiple imputation and scenario analyses addressed bias due to attrition or missing data. RESULTS: The cohort included 5566 women (mean ± standard deviation: 66.8 ± 9.3 years) and 2187 men (66.3 ± 9.5 years) with the mean baseline CFI scores of 0.15 ± 0.11 and 0.12 ± 0.10, respectively. Incident fractures and obesity most strongly predicted frailty progression in multivariable analyses. The impact of fractures differed between the sexes. With each incident hip fracture, the adjusted mean CFI accelerated per 5 years by 0.07 in women (95% confidence interval [CI]: 0.03 to 0.11) and by 0.12 in men (95% CI: 0.08 to 0.16). An incident vertebral fracture increased frailty in women (0.05, 95% CI: 0.02 to 0.08) but not in men (0.01, 95% CI: -0.07 to 0.09). Irrespective of sex and prevalent fractures, baseline obesity was associated with faster frailty progression: a 5-year increase in the adjusted mean CFI ranged from 0.01 in overweight (BMI: 25.0 to 29.9 kg/m2) to 0.10 in obese individuals (BMI: ≥ 40 kg/m2). Greater physical activity and better HRQL decreased frailty over time. The results remained robust in scenario analyses. CONCLUSIONS: Older women and men with new vertebral fractures, hip fractures or obesity represent high-risk groups that should be considered for frailty interventions.

Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis.

BACKGROUND: Adults who require long-term anticoagulation with low-molecular-weight heparin (LMWH) such as cancer patients or the elderly may be at increased risk of fractures. OBJECTIVE: To determine the effects of LMWH therapy of at least 3 months' duration on fractures and bone mineral density (BMD) in non-pregnant adult populations. METHODS: We systematically reviewed electronic databases (e.g., MEDLINE, EMBASE), conferences and bibliographies until June 2015 and included comparative studies in non-pregnant adult populations that examined the effects of LMWH (≥3 months) on fractures and BMD. We synthesized evidence qualitatively and used random-effects meta-analysis to quantify the effect of LMWH on fractures. RESULTS: Sixteen articles reporting 14 studies were included: 10 clinical trials (n = 4865 participants) and four observational cohort studies (3 prospective, n = 221; 1 retrospective, n = 30). BMD and fractures were secondary outcomes in the majority of trials, while they were primary outcomes in the majority of observational studies. In participants with venous thromboembolism and underlying cardiovascular disease or cancer (5 RCTs, n = 2280), LMWH for 3-6 months did not increase the relative risk of all fractures at 6-12 months compared to unfractionated heparin, oral vitamin K antagonists or placebo [pooled risk ratio (RR) = 0.58, 95 % CI: 0.23-1.43; I(2) = 12.5 %]. No statistically significant increase in the risk of fractures at 6-12 months was found for cancer patients (RR = 1.08, 95 % CI: 0.31-3.75; I(2) = 4.4 %). Based on the data from two prospective cohort studies (n = 166), LMWH for 3-24 months decreased mean BMD by 2.8-4.8 % (depending on the BMD site) compared to mean BMD decreases of 1.2-2.5 % with oral vitamin K antagonists. CONCLUSIONS: LMWH for 3-6 months may not increase the risk of fractures, but longer exposure for up to 24 months may adversely affect BMD. Clinicians should consider monitoring BMD in adults on long-term LMWH who are at increased risk of bone loss or fracture.

A tutorial on Bayesian bivariate meta-analysis of mixed binary-continuous outcomes with missing treatment effects.

Bivariate random-effects meta-analysis (BVMA) is a method of data synthesis that accounts for treatment effects measured on two outcomes. BVMA gives more precise estimates of the population mean and predicted values than two univariate random-effects meta-analyses (UVMAs). BVMA also addresses bias from incomplete reporting of outcomes. A few tutorials have covered technical details of BVMA of categorical or continuous outcomes. Limited guidance is available on how to analyze datasets that include trials with mixed continuous-binary outcomes where treatment effects on one outcome or the other are not reported. Given the advantages of Bayesian BVMA for handling missing outcomes, we present a tutorial for Bayesian BVMA of incompletely reported treatment effects on mixed bivariate outcomes. This step-by-step approach can serve as a model for our intended audience, the methodologist familiar with Bayesian meta-analysis, looking for practical advice on fitting bivariate models. To facilitate application of the proposed methods, we include our WinBUGS code. As an example, we use aggregate-level data from published trials to demonstrate the estimation of the effects of vitamin K and bisphosphonates on two correlated bone outcomes, fracture, and bone mineral density. We present datasets where reporting of the pairs of treatment effects on both outcomes was 'partially' complete (i.e., pairs completely reported in some trials), and we outline steps for modeling the incompletely reported data. To assess what is gained from the additional work required by BVMA, we compare the resulting estimates to those from separate UVMAs. We discuss methodological findings and make four recommendations. Copyright © 2015 John Wiley & Sons, Ltd.

A methodological guide for implementing and interpreting results of probabilistic analysis.

INTRODUCTION: Probabilistic analysis, also referred to as probabilistic sensitivity analysis (PSA), is used extensively in cost-effectiveness evaluations of health technologies. We present methodological guidance for implementing probabilistic analysis and interpreting its results for policy and decision-making. METHODS: We review the methodological issues related to common practices in probabilistic analysis, explore aspects that are currently not widely addressed in the health economics literature, and provide an overview of recent methodological developments. RESULTS: We use examples to highlight the advantages and disadvantages of common tools used for presenting probabilistic analysis results, including the cost-effectiveness acceptability curve (CEAC), cost-effectiveness acceptability frontier (CEAF), and value of information (VOI) analysis. We raise and address issues related to using Monte Carlo standard error to determine the number of iterations required, the implications of large uncertainty, and the credibility and meaningfulness of small differences in quality-adjusted life-years (QALYs). We then discuss evolving methods in probabilistic analysis, cautious uses of probabilistic analysis, and factors impacting parameter uncertainty. CONCLUSIONS: A deeper understanding of probabilistic analysis methods enables health economists and decision-makers to more effectively address and interpret parameter uncertainty in health economic evaluations, which is essential for making informed policy decisions.

Vitamin K and bone health.

Vitamin K has been purported to play an important role in bone health. It is required for the gamma-carboxylation of osteocalcin (the most abundant noncollagenous protein in bone), making osteocalcin functional. There are 2 main forms (vitamin K1 and vitamin K2), and they come from different sources and have different biological activities. Epidemiologic studies suggest a diet high in vitamin K is associated with a lower risk of hip fractures in aging men and women. However, randomized controlled trials of vitamin K1 or K2 supplementation in white populations did not increase bone mineral density at major skeletal sites. Supplementation with vitamin K1 and K2 may reduce the risk of fractures, but the trials that examined fractures as an outcome have methodological limitations. Large well-designed trials are needed to compare the efficacies of vitamin K1 and K2 on fractures. We conclude that currently there is not enough evidence to recommend the routine use of vitamin K supplements for the prevention of osteoporosis and fractures in postmenopausal women.

Evaluating the correlations of cost and utility parameters from summary statistics for probabilistic analysis in economic evaluations.

OBJECTIVES: The correlations between economic modeling input parameters directly impact the variance and may impact the expected values of model outputs. However, correlation coefficients are not often reported in the literature. We aim to understand the correlations between model inputs for probabilistic analysis from summary statistics. METHODS: We provide proof that for correlated random variables X and Y (e.g. inpatient visits and outpatient visits), the Pearson correlation coefficients of sample means and samples are equal to each other (corrX,Y=corrX-,Y-). Therefore, when studies report summary statistics of correlated parameters, we can quantify the correlation coefficient between parameters. RESULTS: We use examples to illustrate how to estimate the correlation coefficient between the incidence rates of non-severe and severe hypoglycemia events, and the common coefficient of five cost components for patients with diabetic foot ulcers. We further introduce three types of correlations for utilities and provide two examples to estimate the correlations for utilities based on published data. We also evaluate how correlations between cost parameters and utility parameters impact the cost-effectiveness results using a Markov model for major depression. CONCLUSION: Incorporation of the correlations can improve the precision of cost-effectiveness results and increase confidence in evidence-based decision-making. Further empirical evidence is warranted.

Examining the correlation between treatment effects in clinical trials and economic modeling.

INTRODUCTION: Many diseases have a sequential treatment pathway. Compared with patients without previous treatment, patients who fail initial treatment may have lower success rates with a second treatment. This phenomenon can be explained by a correlation between treatment effects. METHODS: We developed a statistical model of covariance for the underlying unobserved correlation between treatments and established a mathematical expression for the magnitude of the latent correlation term. We conducted a simulation study of clinical trials to investigate the correlation between two treatments and explored clinical examples based on published literature to illustrate the identification and evaluation of these correlations. RESULTS: Our simulation study confirmed that a treatment correlation reduces the probability of success for the second treatment, compared with no correlation. We found that treatment correlations may be observable in clinical trials, such as for depression and lung cancer, and the magnitude of correlation may be estimated. We illustrated that treatment correlations can be incorporated into an economic model, with possible impacts on cost-effectiveness results. Additional applications of correlation concepts are also discussed. CONCLUSIONS: We evaluated the correlation between treatment effects and our approach can be applied to clinical trial design and economic modeling of sequential clinical treatment pathways.

Comparison of the expected rewards between probabilistic and deterministic analyses in a Markov model.

Objectives: In Markov models that evaluate the cost-effectiveness of health-care technologies, it is generally recommended to use probabilistic analysis instead of deterministic analysis. We sought to compare the performance of probabilistic and deterministic analysis in estimating the expected rewards in a Markov model.Methods: We applied Jensen's inequality to compare the expected Markov rewards between probabilistic and deterministic analysis and conducted a simulation study to compare the bias and accuracy between the two approaches.Results: We provided mathematical justification why probabilistic analysis is associated with greater Markov rewards (life-years and quality-adjusted life-years) compared with deterministic analysis. In our simulations, probabilistic analyses tended to generate greater life-years, bias, and mean square error for the estimated rewards compared with deterministic analyses. When the expected values of transition probabilities were the same, weaker evidence derived from smaller sample sizes resulted in larger Markov rewards compared with stronger evidence derived from larger sample sizes. When longer time horizons were applied in cases of weak evidence, there was a substantial increase in bias where the rewards in both probabilistic and deterministic analysis were overestimated.Conclusion: Authors should be aware that probabilistic analysis may lead to increased bias when the evidence is weak.

Incident Fragility Fractures Have a Long-Term Negative Impact on Health-Related Quality of Life of Older People: The Canadian Multicentre Osteoporosis Study.

Although the short-term impact of incident fragility fractures on health-related quality of life (HRQL) of older people has been confirmed, we lack long-term evidence. We explored the impact of incident fragility fractures on HRQL, among people aged 50 years and older, using 10-year prospective data from the Canadian Multicentre Osteoporosis Study (CaMos). This study was based on data from 7753 (2187 men and 5566 women) participants of CaMos. The HRQL, measured through the Health Utility Index (HUI), was captured at baseline and year 10. The incident fragility fractures were recorded over 10 years of follow-up at spine, hip, rib, shoulder, pelvis, or forearm. Multivariable regression analysis was conducted to measure the mean difference, termed as deficit, in the HUI scores for participants with and without fractures. We examined the effects of single or multiple fragility fractures, time (fractures that occurred between year 1 to 5 and 6 to 10) and recovery to the prefracture level. Incident spine and hip fractures were associated with significant deficits (varied from -0.19 to -0.07) on the HUI scores. Hip and spine fractures were associated with negative impact on mobility, self-care, and ambulation. Fractures that occurred closer to the follow-up assessment were associated with significant impact on HRQL compared to fractures occurring a long time before it, except for hip fracture (deficits lasted 5 years or longer). Similarly, multiple hip (-0.14), spine (-0.16), and rib (-0.21) fractures significantly impacted the HRQL of women. Women with a hip fracture never recovered to their prefracture level score (OR = 0.41; 95% confidence interval [CI], 0.19 to 0.98). Our analysis suggests that single and multiple hip fractures as well as multiple spine and rib fractures strongly impact the HRQL of older people over a prolonged period of time. © 2019 American Society for Bone and Mineral Research.

Getting fit for hip and knee replacement: a protocol for the Fit-Joints pilot randomized controlled trial of a multi-modal intervention in frail patients with osteoarthritis.

BACKGROUND: Joint replacement provides significant improvements in pain, physical function, and quality of life in patients with osteoarthritis. With a growing body of evidence indicating that frailty can be treated, it is important to determine whether targeting frailty reduction in hip and knee replacement patients improves post-operative outcomes. OBJECTIVES: The primary objective is to examine the feasibility of a parallel group RCT comparing a preoperative multi-modal frailty intervention to usual care in pre-frail/frail older adults undergoing elective unilateral hip or knee replacements. The secondary objectives areTo explore potential efficacy of the multi-modal frailty intervention in improving frailty and mobility between baseline and 6 weeks post-surgery using Fried frailty phenotype and short performance physical battery (SPPB) respectively.To explore potential efficacy of the multi-modal frailty intervention on post-operative healthcare services use. METHODS/DESIGN: In a parallel group pilot RCT, participants will be recruited from the Regional Joint Assessment Program in Hamilton, Canada. Participants who are (1) ≥ 60 years old; (2) pre-frail (score of 1 or 2) or frail (score of 3-5; Fried frailty phenotype); (3) having elective unilateral hip or knee replacement; and (4) having surgery wait times between 3 and 10 months will be recruited and randomized to either the intervention or usual care group. The multi-modal frailty intervention components will include (1) tailored exercise program (center-based and/or home-based) with education and cognitive behavioral change strategies; (2) protein supplementation; (3) vitamin D supplementation; and (4) medication review. The main comparative analysis will take place at 6 weeks post-operative. The outcome assessors, data entry personnel, and data analysts are blinded to treatment allocation. Assessments: feasibility will be assessed by recruitment rate, retention rate, and data collection completion. Frailty and healthcare use and other clinical outcomes will be assessed. The study outcomes will be collected at the baseline, 1 week pre-operative, and 6 weeks and 6 months post-operative. DISCUSSION: This is the first study to examine the feasibility of multi-modal frailty intervention in pre-frail/frail older adults undergoing hip or knee replacement. This study will inform the planning and designing of multi-modal frailty interventional studies in hip and knee replacement patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02885337.

Women trafficked into prostitution: determinants, human rights and health needs.

Human trafficking is an international challenge that increasingly affects industrialized countries. It represents a gross violation of a person's right to liberty and freedom of movement, and is often accompanied by violence and degrading treatment which can have detrimental effects on health. In this article, we review the definition and extent of human trafficking, and focus on the human rights abuses and determinants of trafficking in women. Mental health and other health outcomes are reviewed, and differences between countries in organized activities for victim assistance and protection are assessed. Finally, we discuss the roles of mental health and other healthcare providers in identifying and helping trafficked women, and recommend a tailored multidisciplinary approach for victim assistance.

The reporting quality of abstracts of stepped wedge randomized trials is suboptimal: A systematic survey of the literature.

BACKGROUND: The stepped wedge trial (SWT) design is a type of the randomized clinical trial (RCT) design in which clusters or individuals are randomly and sequentially crossed over from control to intervention over a number of time periods. Trials using SWT design have become increasingly popular in medical, behavioral and social sciences research. Therefore, complete and transparent reporting of these studies is crucial. In particular, the quality of the abstracts of their reports is important because these may be the only accessible sources for their results. OBJECTIVE: The aims of this survey were to evaluate the reporting quality of SWT abstracts and to identify factors contributing to better reporting quality. METHODS: We performed literature searches to identify relevant articles in English published from November 1987 to October 2016 in the following electronic databases: Medline, Embase, Web of Science, CINAHL, and PsycINFO. At least two reviewers examined the quality of abstract reporting using the 17-item CONSORT (CONsolidated Standards Of Reporting Trials) Extension for Abstracts tool. Poisson regression models for incidence rate ratio (IRR) were used to identify factors associated with reporting quality (e.g., CONSORT endorsement, the number of authors, abstract format). RESULTS: A total of 92 eligible articles were identified. Only 6 from the 17 items were reported in more than 80% of the articles (e.g., the statement of conclusions, contact details for the corresponding author). In the multivariable analysis, the year of publication since 2008 (IRR: 1.16; 95% confidence interval (CI): 1.02, 1.33), journal endorsement of the CONSORT Statement (IRR: 1.15; 95% CI: 1.01, 1.31), and multiple authorship (IRR 1.13, 95% CI: 1.01, 1.27) were significantly associated with better reporting quality. CONCLUSION: The quality of reporting of SWT abstracts was suboptimal, although there have been some significant improvements since 2008. Endorsement of the CONSORT Statement by journals is an essential element of improvement strategies. Also, multiple authorship is significantly associated with better quality of abstract reporting.

Reporting quality of stepped wedge design randomized trials: a systematic review protocol.

BACKGROUND: Stepped wedge design (SWD) is a cluster randomized controlled trial (RCT) design that sequentially rolls out intervention to all clusters at varying time points. Being a relatively new design method, reporting quality has yet to be explored, and this review will seek to fill this gap in knowledge. OBJECTIVES: The objectives of this review are: 1) to assess the quality of SWD trial reports based on the CONSORT guidelines or CONSORT extension to cluster RCTs; 2) to assess the completeness of reporting of SWD trial abstracts using the CONSORT extension for abstracts; 3) to assess the reporting of sample size details in SWD trial reports or protocols; 4) to assess the completeness of reporting of SWD trial protocols according to SPIRIT guidelines; 5) to assess the consistency between the trial registration information and final SWD trial reports; and 6) to assess the consistency of what is reported in the abstracts and main text of the SWD trial reports. We will also explore factors that are associated with the completeness of reporting. METHODS: We will search MEDLINE, EMBASE, Web of Science, CINAHL, and PsycINFO for all randomized controlled trials utilizing SWD. Details from eligible papers will be extracted in duplicate. Demographic statistics obtained from the data extraction will be analyzed to answer the primary objectives pertaining to the reporting quality of several aspects of a published paper, as well as to explore possible temporal trends and consistency between abstracts, trial registration information, and final published articles. DISCUSSION: Findings from this review will establish the reporting quality of SWD trials and inform academics and clinicians on their completeness and consistency. Results of this review will influence future trials and improve the overall quality and reporting of SWD trials.

Odanacatib for the treatment of osteoporosis.

INTRODUCTION: Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib , are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue. AREAS COVERED: The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib. EXPERT OPINION: Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.

Effect of odanacatib on BMD and fractures: estimates from Bayesian univariate and bivariate meta-analyses.

CONTEXT: Odanacatib (ODN), a selective cathepsin-K inhibitor, was found to increase bone mineral density (BMD); the effect on fractures is based on adverse event reports. OBJECTIVE: To estimate current effects and predict future effects of ODN on BMD and fractures. DATA SOURCES: Electronic databases (Medline, EMBASE, Cochrane Library), conference proceedings, and bibliographies. STUDY SELECTION: Trials that compared ODN 50 mg/wk to placebo for at least 1 year and reported changes in BMD or fractures. Meta-analysis: Two bone outcomes were pooled as independent and as joint outcomes in Bayesian univariate and bivariate random-effects models. DATA SYNTHESIS: Of 32 potentially eligible articles, six citations describing four trials (993 patients) were included. ODN for 3 years increased mean BMD at the lumbar spine by 5.0% (95% credible interval [CrI], 2.7, 7.5), total hip by 3.6% (95% CrI, 1.6, 5.9), and femoral neck (FN) by 3.6% (95% CrI, 1.6, 5.7). In a future trial of 3-year duration, the predicted mean increase in BMD, adjusted for the effect on fractures, was 4.9% for lumbar spine (95% CrI, 2.5, 7.4), 3.4% for total hip (95% CrI, 1.7, 5.2), and 3.5% for FN (95% CrI, 1.8, 5.3). After accounting for the effect on FN BMD, ODN for 3 years was associated with a population odds ratio of 0.38 (95% CrI, 0.1, 0.8). In a future trial, the odds ratio was 0.41 (95% CrI, 0.1, 1.1). The probability of benefit on fractures was 96-99%. The estimates remained robust in sensitivity analyses. CONCLUSIONS: Our analyses suggest that ODN will increase BMD and decrease all fractures in the fracture outcome trial; however, direct demonstration of this antifracture efficacy is needed.

The choice of a noninformative prior on between-study variance strongly affects predictions of future treatment effect.

PURPOSE: Bayesian random-effects meta-analyses require the analyst to specify the prior distribution for between-study variance of the treatment effect. We assessed the sensitivity of prediction and other outputs of the meta-analysis to the choice of this prior. METHODS: We reanalyzed 7 published meta-analyses (5-14 trials) with rare (event rates <5%), moderate (15%-50%), and frequent binary outcomes (>50%). We examined 10 noninformative priors: inverse gamma on between-study variance (τ (2)), 2 uniforms on each of the between-study standard deviation (τ) and τ (2), uniform shrinkage on τ (2), DuMouchel shrinkage on τ, half-normal on τ (2), and half-normal priors on τ with large and small variances. For each analysis, we calculated the posterior distributions for τ, the population treatment effect in current studies, and the predicted treatment effect in a future study. We assessed goodness of fit using total residual deviance, the deviance information criterion, and predictive deviance (by cross-validations). RESULTS: According to total residual deviance, the best-fitting priors were uniform on τ (2). According to predictive deviance, half-normal on τ (2) and the shrinkage priors were optimal. Across analyses with the 10 priors, there were no important differences in the posteriors for the population treatment effect, but there were substantial differences in the posteriors for τ and predictions. The priors that fitted best according to predictive deviance resulted in less uncertainty around predictions of future treatment effect. CONCLUSIONS: In this sample of Bayesian meta-analyses with binary outcomes, the choice of noninformative prior for between-study variance affected model fit and the predictions of future treatment effect. When the predictive distribution is of interest, we highly recommend examination of multiple prior distributions for between-study variance, especially the half-normal on τ (2) and the shrinkage priors.