Abstract An increasing number of organizations worldwide are using new and improved standards for developing trustworthy clinical guidelines. One of such approaches, developed by the Grading of ...Recommendations Assessment, Development, and Evaluation (GRADE) working group, offers systematic and transparent guidance in moving from evidence to recommendations. The GRADE strategy concentrates on four factors: the balance between benefits and harms, the certainty of the evidence, values and preferences, and resource considerations. However, it also considers issues around feasibility, equity, and acceptability of recommendations. GRADE distinguishes two types of recommendations: strong and weak. Strong recommendations reflect a clear preference for one alternative and should apply to all or almost all patients, obviating the need for a careful review of the evidence with each patient. Weak recommendations are appropriate when there is a close balance between desirable and undesirable consequences of alternative management strategies, uncertainty regarding the effects of the alternatives, uncertainty or variability in patients' values and preferences, or questionable cost-effectiveness. Weak recommendations usually require accessing the underlying evidence and a shared decision-making approach. Clinicians using GRADE recommendations should understand the meaning of the strength of the recommendation, be able to critically appraise the recommendation, and apply trustworthy recommendations according to their strength.
This article describes considerations for addressing intransitivity when assessing the certainty of the evidence from network meta-analysis (NMA) using the Grading of Recommendations Assessment, ...Development, and Evaluation (GRADE) approach. Intransitivity is induced by effect modification, that is, when the magnitude of the effect between an intervention and outcome differs depending on the level of another factor.
To develop this GRADE concept paper, the lead authors conducted iterative discussions, computer simulations, and presentations to the GRADE project group and at GRADE working group meetings. The GRADE Working Group formally approved the article in July 2022.
NMA authors can have a higher or a lower threshold to rate down the certainty of the evidence due to intransitivity, which depends on the extent of their concerns regarding the trustworthiness of indirect comparisons, and their view of the relative problems with rating down excessively or insufficiently. NMA authors should consider three main factors when addressing intransitivity: the credibility of effect modification, the strength of the effect modification, and the distribution of effect modifiers across the direct comparisons. To avoid double counting limitations of the evidence, authors should consider the relationship between intransitivity and other GRADE domains.
NMA authors face theoretic and pragmatic challenges and in most situations need to assess intransitivity without the availability of empirical data. Thus, explicitness regarding perspective is crucial.
Observational studies have shown that the El Niño–Southern Oscillation (ENSO) exerts an influence on the Quasi-Biennial Oscillation (QBO). The downward propagation of the QBO tends to speed up and ...slow down during El Niño and La Niña, respectively. Recent results from general circulation models have indicated that the ENSO modulation of the QBO requires a relatively high horizontal resolution, and that it does not show up in the climate models with parameterized but temporally constant gravity wave sources. Here, we demonstrate that the NASA Goddard Institute for Space Studies (GISS) E2.2 models can capture the observed ENSO modulation of the QBO period with a horizontal resolution of 2∘ latitude by 2.5∘ longitude but with its gravity wave sources being parameterized interactively. This is because El Niño events lead to more vigorous gravity wave sources generating more absolute momentum fluxes over the equatorial belt, as well as less filtering of these waves into the tropical lower stratosphere through a weakening of the Walker circulation. Various components of the ENSO system, such as the sea surface temperatures, the convective activities, and the Walker circulation, are intimately involved in the generation and propagation of parameterized gravity waves, through which ENSO modulates the QBO period in GISS E2.2 models.
Nadofaragene firadenovec is a gene therapy for bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) undergoing Food and Drug Administration review. Pembrolizumab is ...approved for treating patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS). We evaluated the cost-effectiveness of these treatments compared with a hypothetical therapeutic alternative, at a willingness-to-pay threshold of $150 000 per quality-adjusted life-year (QALY) gained, in CIS and non-CIS BCG-unresponsive NMIBC populations.
We developed a Markov cohort simulation model with a 3-month cycle length and lifetime horizon to estimate the total costs, QALYs, and cost per additional QALY from the health sector perspective. Clinical inputs were informed by results of single-arm clinical trials evaluating the treatments, and systematic literature reviews were conducted to obtain other model inputs. Sensitivity analyses were conducted to assess uncertainty in model results.
Nadofaragene firadenovec, at a placeholder price 10% higher than the price of pembrolizumab, had an incremental cost-effectiveness ratio of $263 000 and $145 000 per QALY gained in CIS and non-CIS populations, respectively. Pembrolizumab had an incremental cost-effectiveness ratio of $168 000 per QALY gained for CIS. A 5.4% reduction in pembrolizumab’s price would make it cost-effective. The model was sensitive to many inputs, especially to the probabilities of disease progression, initial treatment response and durability, and drug price.
The cost-effectiveness of nadofaragene firadenovec will depend upon its price. Pembrolizumab, although not cost-effective in our base-case analysis, is an important alternative in this population with an unmet medical need. Comparative trials of these treatments are warranted to better estimate cost-effectiveness.
•There are few therapeutic alternatives for the treatment of bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer. Although cystectomy is potentially curative, many patients are ineligible for or unwilling to undergo cystectomy. Nadofaragene firadenovec and pembrolizumab are new bladder-sparing treatments.•This study evaluated the lifetime cost-effectiveness of nadofaragene firadenovec and pembrolizumab from the US health sector perspective.•Using a placeholder price, nadofaragene firadenovec was cost-effective in the non–carcinoma in situ (CIS) population but not in the CIS population. Pembrolizumab, at its current price, was not cost-effective in the CIS population. Cost per quality-adjusted life-year gained and threshold price estimates can aid drug pricing negotiations between payers and drug manufacturers.
We describe how consideration of external evidence may play an important role in judging certainty in the process of establishing the certainty of the evidence. Our example is a network meta-analysis ...(NMA) addressing treatment for Ebola virus disease, which informed a World Health Organization guideline.
Through Grading of Recommendations Assessment, Development, and Evaluations (GRADE) project group iterative online, in-person and email discussions, we developed this GRADE concept and obtained approval from the GRADE working group. Using the null as a threshold, we rated our certainty for network estimates in mortality, including consideration of evidence external to the NMA (i.e., did not meet eligibility criteria) and formal logical construction.
Based on the existing GRADE guidance, we rated the network estimate for one indirect comparison as low certainty. The formal logical construction that lead us reevaluate the certainty of the evidence is as follows: if A is superior to B, and B is not inferior to C, then A must be superior to C. After considering the logic and the external indirect evidence, we concluded at least moderate certainty for the comparison.
Systematic review authors and guideline developers should apply the fundamental logical construction for indirect comparisons and consider compelling external evidence in NMA certainty ratings.
Simulations of the preindustrial and doubled CO₂ climates are made with the GISS Global Climate Middle Atmosphere Model 3 using two different estimates of the absolute solar irradiance value: a ...higher value measured by solar radiometers in the 1990s and a lower value measured recently by the Solar Radiation and Climate Experiment. Each of the model simulations is adjusted to achieve global energy balance; without this adjustment the difference in irradiance produces a global temperature change of 0.4°C, comparable to the cooling estimated for the Maunder Minimum. The results indicate that by altering cloud cover the model properly compensates for the different absolute solar irradiance values on a global level when simulating both preindustrial and doubled CO₂ climates. On a regional level, the preindustrial climate simulations and the patterns of change with doubled CO₂ concentrations are again remarkably similar, but there are some differences. Using a higher absolute solar irradiance value and the requisite cloud cover affects the model’s depictions of high-latitude surface air temperature, sea level pressure, and stratospheric ozone, as well as tropical precipitation. In the climate change experiments it leads to an underestimation of North Atlantic warming, reduced precipitation in the tropical western Pacific, and smaller total ozone growth at high northern latitudes. Although significant, these differences are typically modest compared with the magnitude of the regional changes expected for doubled greenhouse gas concentrations. Nevertheless, the model simulations demonstrate that achieving the highest possible fidelity when simulating regional climate change requires that climate models use as input the most accurate (lower) solar irradiance value.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The U.S. Climate Variability and Predictability (CLIVAR) working group on drought recently initiated a series of global climate model simulations forced with idealized SST anomaly patterns, designed ...to address a number of uncertainties regarding the impact of SST forcing and the role of land–atmosphere feedbacks on regional drought. The runs were carried out with five different atmospheric general circulation models (AGCMs) and one coupled atmosphere–ocean model in which the model was continuously nudged to the imposed SST forcing. This paper provides an overview of the experiments and some initial results focusing on the responses to the leading patterns of annual mean SST variability consisting of a Pacific El Niño–Southern Oscillation (ENSO)-like pattern, a pattern that resembles the Atlantic multidecadal oscillation (AMO), and a global trend pattern.
One of the key findings is that all of the AGCMs produce broadly similar (though different in detail) precipitation responses to the Pacific forcing pattern, with a cold Pacific leading to reduced precipitation and a warm Pacific leading to enhanced precipitation over most of the United States. While the response to the Atlantic pattern is less robust, there is general agreement among the models that the largest precipitation response over the United States tends to occur when the two oceans have anomalies of opposite signs. Further highlights of the response over the United States to the Pacific forcing include precipitation signal-to-noise ratios that peak in spring, and surface temperature signal-to-noise ratios that are both lower and show less agreement among the models than those found for the precipitation response. The response to the positive SST trend forcing pattern is an overall surface warming over the world’s land areas, with substantial regional variations that are in part reproduced in runs forced with a globally uniform SST trend forcing. The precipitation response to the trend forcing is weak in all of the models.
It is hoped that these early results, as well as those reported in the other contributions to this special issue on drought, will serve to stimulate further analysis of these simulations, as well as suggest new research on the physical mechanisms contributing to hydroclimatic variability and change throughout the world.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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