74 research outputs found
Characterization and valuation of uncertainty of calibrated parameters in stochastic decision models
We evaluated the implications of different approaches to characterize
uncertainty of calibrated parameters of stochastic decision models (DMs) in the
quantified value of such uncertainty in decision making. We used a
microsimulation DM of colorectal cancer (CRC) screening to conduct a
cost-effectiveness analysis (CEA) of a 10-year colonoscopy screening. We
calibrated the natural history model of CRC to epidemiological data with
different degrees of uncertainty and obtained the joint posterior distribution
of the parameters using a Bayesian approach. We conducted a probabilistic
sensitivity analysis (PSA) on all the model parameters with different
characterizations of uncertainty of the calibrated parameters and estimated the
value of uncertainty of the different characterizations with a value of
information analysis. All analyses were conducted using high performance
computing resources running the Extreme-scale Model Exploration with Swift
(EMEWS) framework. The posterior distribution had high correlation among some
parameters. The parameters of the Weibull hazard function for the age of onset
of adenomas had the highest posterior correlation of -0.958. Considering full
posterior distributions and the maximum-a-posteriori estimate of the calibrated
parameters, there is little difference on the spread of the distribution of the
CEA outcomes with a similar expected value of perfect information (EVPI) of
\$653 and \$685, respectively, at a WTP of \$66,000/QALY. Ignoring correlation
on the posterior distribution of the calibrated parameters, produced the widest
distribution of CEA outcomes and the highest EVPI of \$809 at the same WTP.
Different characterizations of uncertainty of calibrated parameters have
implications on the expect value of reducing uncertainty on the CEA. Ignoring
inherent correlation among calibrated parameters on a PSA overestimates the
value of uncertainty.Comment: 17 pages, 6 figures, 3 table
VLA 1.4 GHz Catalogs of the Abell 370 and Abell 2390 Cluster Fields
We present 1.4 GHz catalogs for the cluster fields Abell 370 and Abell 2390
observed with the Very Large Array. These are two of the deepest radio images
of cluster fields ever taken. The Abell 370 image covers an area of 40'x40'
with a synthesized beam of ~1.7" and a noise level of ~5.7 uJy near field
center. The Abell 2390 image covers an area of 34'x34' with a synthesized beam
of ~1.4" and a noise level of ~5.6 uJy near field center. We catalog 200
redshifts for the Abell 370 field. We construct differential number counts for
the central regions (radius < 16') of both clusters. We find that the faint
(S_1.4GHz < 3 mJy) counts of Abell 370 are roughly consistent with the highest
blank field number counts, while the faint number counts of Abell 2390 are
roughly consistent with the lowest blank field number counts. Our analyses
indicate that the number counts are primarily from field radio galaxies. We
suggest that the disagreement of our counts can be largely attributed to cosmic
variance.Comment: 13 pages, accepted for publication in ApJ
Comparative economic evaluation of data from the ACRIN national CT colonography trial with three cancer intervention and surveillance modeling network microsimulations
Purpose: To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. Materials and Methods: Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U.S. health care sector perspective, assuming a 3% discount rate. Results: CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: 50 000 per life-year gained. Conclusion: All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions
Emulator-based Bayesian calibration of the CISNET colorectal cancer models
PURPOSE: To calibrate Cancer Intervention and Surveillance Modeling Network (CISNET) 's SimCRC, MISCAN-Colon, and CRC-SPIN simulation models of the natural history colorectal cancer (CRC) with an emulator-based Bayesian algorithm and internally validate the model-predicted outcomes to calibration targets.METHODS: We used Latin hypercube sampling to sample up to 50,000 parameter sets for each CISNET-CRC model and generated the corresponding outputs. We trained multilayer perceptron artificial neural networks (ANN) as emulators using the input and output samples for each CISNET-CRC model. We selected ANN structures with corresponding hyperparameters (i.e., number of hidden layers, nodes, activation functions, epochs, and optimizer) that minimize the predicted mean square error on the validation sample. We implemented the ANN emulators in a probabilistic programming language and calibrated the input parameters with Hamiltonian Monte Carlo-based algorithms to obtain the joint posterior distributions of the CISNET-CRC models' parameters. We internally validated each calibrated emulator by comparing the model-predicted posterior outputs against the calibration targets.RESULTS: The optimal ANN for SimCRC had four hidden layers and 360 hidden nodes, MISCAN-Colon had 4 hidden layers and 114 hidden nodes, and CRC-SPIN had one hidden layer and 140 hidden nodes. The total time for training and calibrating the emulators was 7.3, 4.0, and 0.66 hours for SimCRC, MISCAN-Colon, and CRC-SPIN, respectively. The mean of the model-predicted outputs fell within the 95% confidence intervals of the calibration targets in 98 of 110 for SimCRC, 65 of 93 for MISCAN, and 31 of 41 targets for CRC-SPIN.CONCLUSIONS: Using ANN emulators is a practical solution to reduce the computational burden and complexity for Bayesian calibration of individual-level simulation models used for policy analysis, like the CISNET CRC models.</p
NordICC Trial Results in Line With Expected Colorectal Cancer Mortality Reduction After Colonoscopy:A Modeling Study
Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With a Blood Test That Meets the Centers for Medicare & Medicaid Services Coverage Decision
Background & Aims: A blood-based colorectal cancer (CRC) screening test may increase screening participation. However, blood tests may be less effective than current guideline-endorsed options. The Centers for Medicare & Medicaid Services (CMS) covers blood tests with sensitivity of at least 74% for detection of CRC and specificity of at least 90%. In this study, we investigate whether a blood test that meets these criteria is cost-effective. Methods: Three microsimulation models for CRC (MISCAN-Colon, CRC-SPIN, and SimCRC) were used to estimate the effectiveness and cost-effectiveness of triennial blood-based screening (from ages 45 to 75 years) compared to no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with an FIT assay, and colonoscopy screening every 10 years. The CMS coverage criteria were used as performance characteristics of the hypothetical blood test. We varied screening ages, test performance characteristics, and screening uptake in a sensitivity analysis. Results: Without screening, the models predicted 77â88 CRC cases and 32â36 CRC deaths per 1000 individuals, costing 5.8 million. Compared to no screening, blood-based screening was cost-effective, with an additional cost of 43,700 per quality-adjusted life-year gained (QALYG). However, compared to FIT, triennial stool DNA testing combined with FIT, and colonoscopy, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT remained more effective (+5â24 QALYG) and less costly (â3.5 million) than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT. Conclusion: Even with higher screening uptake, triennial blood-based screening, with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with established strategies for colorectal cancer screening.</p
Cost-effectiveness of a multitarget stool DNA test for colorectal cancer screening of Medicare beneficiaries
Background
In 2014, the Centers for Medicare and Medicaid Services (CMS) began covering a multitarget stool DNA (mtSDNA) test for colorectal cancer (CRC) screening of Medicare beneficiaries. In this study, we evaluate
Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells.
Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the core cell cycle machinery: that is, the deubiquitylation of the G1 cyclin D1 (CCND1). Deubiquitylation by USP22 protects CCND1 from proteasome-mediated degradation and occurs separately from the canonical phosphorylation/ubiquitylation mechanism previously shown to regulate CCND1 stability. We demonstrate that control of CCND1 is a key mechanism by which USP22 mediates its known role in cell cycle progression. Finally, USP22 and CCND1 levels correlate in patient lung and colorectal cancer samples and our preclinical studies indicate that targeting USP22 in combination with CDK inhibitors may offer an approach for treating cancer patients whose tumors exhibit elevated CCND1
Characterizing blood metabolomics profiles associated with self-reported food intakes in female twins
Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [â„1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations
Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies
First published: 16 February 202
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