Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease: effect of grain fortification and beyond.

CONTEXT: A high homocysteine level has been identified as an independent modifiable risk factor for coronary heart disease (CHD) events and death. Since January 1998, the US Food and Drug Administration has required that all enriched grain products contain 140 microg of folic acid per 100 g, a level considered to decrease homocysteine levels. OBJECTIVES: To examine the potential effect of grain fortification with folic acid on CHD events and to estimate the cost-effectiveness of additional vitamin supplementation (folic acid and cyanocobalamin) for CHD prevention. DESIGN AND SETTING: Cost-effectiveness analysis using the Coronary Heart Disease Policy Model, a validated, state-transition model of CHD events in adults aged 35 through 84 years. Data from the third National Health and Nutrition Examination Survey (NHANES III) were used to estimate age- and sex-specific differences in homocysteine levels. INTERVENTION: Hypothetical comparison between a diet that includes enriched grain products projected to increase folic acid intake by 100 microg/d with the same diet without folic acid fortification; and a comparison between vitamin therapy that consists of 1 mg of folic acid and 0.5 mg of cyanocobalamin and the diet that includes grains fortified with folic acid. MAIN OUTCOME MEASURES: Incidence of myocardial infarction and death from CHD, quality-adjusted life-years (QALYs) saved, and medical costs. RESULTS: Grain fortification with folic acid was predicted to decrease CHD events by 8% in women and 13% in men, with comparable reductions in CHD mortality. The model projected that, compared with grain fortification alone, treating all patients with known CHD with folic acid and cyanocobalamin over a 10-year period would result in 310 000 fewer deaths and lower costs. Over the same 10-year period, providing vitamin supplementation in addition to grain fortification to all men aged 45 years or older without known CHD was projected to save more than 300 000 QALYs, to save more than US $2 billion, and to be the preferred strategy. For women without CHD, the preferred vitamin supplementation strategy would be to treat all women older than 55 years, a strategy projected to save more than 140 000 QALYs over 10 years. CONCLUSIONS: Folic acid and cyanocobalamin supplementation may be cost-effective among many population subgroups and could have a major epidemiologic benefit for primary and secondary prevention of CHD if ongoing clinical trials confirm that homocysteine-lowering therapy decreases CHD event rates.

Consolidation of common parameters from multiple fits in dynamic PET data analysis.

In dynamic positron emission tomography (PET) data analysis, regions of interest (ROI's) are analyzed by fitting a parametric model to the time-activity curve acquired after a radio-labeled tracer has been introduced into the patient's bloodstream. This procedure can be carried out for multiple ROI's and/or multiple injections of the same or a different radiopharmaceutical. The approach presented here takes advantage of prior knowledge that some of the parameters of those multiple fits are the same. Reduction of the total number of parameters to be estimated results in smaller statistical uncertainty for all parameter estimates, especially those common to multiple fits.

Consequences of using a simplified kinetic model for dynamic PET data.

UNLABELLED: We compared a physiological model of 82Rb kinetics in the myocardium with two reduced-order models to determine their usefulness in assessing physiological parameters from dynamic PET data. METHODS: A three-compartment model of 82Rb in the myocardium was used to simulate kinetic PET ROI data. Simulations were generated for eight different blood-flow rates reflecting the physiological range of interest. Two reduced-order models commonly used with myocardial PET studies were fit to the simulated data, and parameters of the reduced-order models were compared with the physiological parameters. Then all three models were fit to the simulated data with noise added. Monte Carlo simulations were used to evaluate and compare the diagnostic utility of the reduced-order models. A description length criterion was used to assess goodness of fit for each model. Finally, fits to simulated data were compared with fits to actual dynamic PET data. RESULTS: Fits of the reduced-order models to the three-compartment model noise-free simulated data produced model misspecification artifacts, such as flow parameter bias and systematic variation with flow in estimates of nonflow parameters. Monte Carlo simulations showed some of the parameter estimates for the two-compartment model to be highly variable at PET noise levels. Fits to actual PET data showed similar variability. One-compartment model estimates of the flow parameter at high and low flow were separated by several s.d.s for both the simulated and the real data. With the two-compartment model, the separation was about one s.d., making it difficult to differentiate a high and a low flow in a single experiment. Fixing nonflow parameters reduced flow parameter variability in the two-compartment model and did not significantly affect variability in the one-compartment model. Goodness of fit indicated that, at realistic noise levels, both reduced-order models fit the simulated data at least as well as the three-compartment model that generated the data. CONCLUSION: The one-compartment reduced-order model of 82Rb dynamic PET data can be used effectively to compare myocardial blood-flow rates at rest and stress levels. The two-compartment model can differentiate flow only if a priori values are used for nonflow parameters.

6-[18F]fluoro-L-m-tyrosine: metabolism, positron emission tomography kinetics, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesions in primates.

The tracer 6-[18F]fluoro-L-m-tyrosine (FMT) was studied with regard to its biochemistry and kinetics, as well as its utility in evaluating brain dopaminergic function in primates before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment using positron emission tomography (PET). Plasma analysis of FMT and its F18-labeled metabolites 6-fluoro-3-hydroxyphenylacetic acid (FPAC) and 6-fluoro-3-hydroxyphenylethylamine (FMA) during PET scanning enabled kinetic analysis of FMT uptake. A separate study examined brain FMT metabolism in MPTP-naive monkeys euthanized 60 or 120 min after FMT injection. Almost 60% of total plasma F-18 activity was associated with FPAC and FMA 120 min after FMT injection. The FMT signal accumulated preferentially in dopaminergic areas such as caudate and putamen. This bilateral FMT signal was disrupted after unilateral intracarotid artery (ICA) MPTP infusion which reduced ipsilateral striatal activity. A three compartment three kinetic rate constant model for FMT uptake revealed reduced FMT decarboxylation (k3) in ipsilateral caudate and putamen after unilateral MPTP although a further decrease was not evident after intravenous MPTP. FPAC was the major F-18 species in all brain regions except in cerebellum where FMT was predominant 60 min post-mortem. FPAC was most concentrated in dopaminergic areas whereas lower levels occurred in areas containing few dopamine terminals. These data demonstrate preferential FMT metabolism and F-18 retention in dopaminergic tissue and support the use of FMT to evaluate normal and abnormal dopaminergic function.

Kinetic analysis of rubidium and thallium as deposited myocardial blood flow tracers in isolated rabbit heart.

Evaluation of myocardial perfusion with tracers such as thallium and rubidium is based on the assumption that tissue tracer content is proportional to flow. The purpose of this study was to evaluate the relationship between flow and tissue tracer content of 201Tl and 83Rb in the isolated perfused rabbit heart. 83Rb (86-day half-life), an isotope that is not used clinically, was used as a subsitute for 82Rb (76-s half-life) to improve the accuracy and precision of data acquisition. The multiple indicator-dilution technique was employed with two independent computational approaches. The first approach explicitly deconvolved 201Tl and 83Rb venous concentration curves by the intravascular reference tracer curve. The second approach used a conventional analysis. Both approaches showed that there was more early washout of 83Rb than 201Tl and that the heart retained 201Tl better than 83Rb within 2 min after isotope introduction. These data indicate that 201Tl is a better perfusion tracer than 83Rb in the isolated rabbit heart.

Strategies for extraction of quantitative data from volumetric dynamic cardiac positron emission tomography data.

The ability of positron emission tomography (PET) to serve as a useful myocardial perfusion indicator is well established. We describe a methodology for obtaining reliable quantitative kinetic parameters from dynamic cardiac PET data. Reconstructed images of the myocardium are subdivided into three-dimensional volumes of interest which are used to obtain quantitative measures of myocardial perfusion over physiologically meaningful anatomical regions. The quantitation technique rigorously models the uncertainty of estimated parameters while compensating for effects such as patient motion and partial volumes to arrive at model parameters with well-established confidence intervals.

Variability and reproducibility of rubidium-82 kinetic parameters in the myocardium of the anesthetized canine.

UNLABELLED: Kinetic analysis of 82Rb dynamic PET data produces quantitative measures which could be used to evaluate ischemic heart disease. These measures have the potential to generate objective comparisons of different patients or the same patient at different times. To achieve this potential, it is essential to determine the variability and reproducibility of the kinetic parameters. METHODS: A total of 48 82Rb dynamic PET datasets were acquired from two pure bred beagles. Each animal underwent eight 82Rb PET studies with essentially the same protocol for three successive weeks. Data were acquired with the Donner 600-Crystal Positron Tomograph (PET600). In each week, single-slice dynamic 82Rb PET datasets were collected with the animal at rest at three different gantry positions separated by 5 mm. Additional dataset were collected after dipyridamole infusion and after administration of aminophylline to induce a return to rest. A two-compartment kinetic model with correction for myocardial vasculature and spillover from the left ventricular blood pool was used to analyze the dynamic datasets. Model parameters for uptake (k1), washout (k2) and vascular fraction (fv) were estimated in 11-14 myocardial regions of interest (ROIs) using a weighted least-squares criterion. Statistical fluctuation due to the PET acquisition process was minimized by using a relatively high 82Rb dose (about 30 mCi) to take advantage of the high count rate capacity of the PET600. RESULTS: The variation in mean k1, where the mean is taken over the myocardial ROIs was 10%-20% (Dog 1) and 15%-50% (Dog 2) among the rest studies conducted on the same date. Similar variation was evident in comparing studies in the same animal for different weeks. CONCLUSION: Spatial and temporal variation in estimates of the uptake rate (k1) of 82Rb in the resting myocardium of the anesthetized canine are small in relation to the functional increase in k1 following dipyridamole infusion.

Simulation of compartmental models for kinetic data from a positron emission tomograph.

Linear compartmental models are used to describe the disposition of radio-labelled compounds in regions of interest in the mammalian body, based on a time sequence of measurements from a positron emission tomograph (PET). In this paper we show how closed form solutions for the model equations have been incorporated into a computer program for simulation and parameter estimation. A typical PET data example is included to illustrate the implementation and compare the closed form method with a numerical ode solution method.

Diminished glucose transport in Alzheimer's disease: dynamic PET studies.

Dynamic positron emission tomography with [18F]fluorodeoxyglucose was used in six patients with Alzheimer's disease (AD) and seven healthy age-matched control subjects to estimate the kinetic parameters K1*, k2*, and k3* that describe glucose transport and phosphorylation. A high-resolution tomograph was used to acquire brain uptake data in one tomographic plane, and a radial artery catheter connected to a plastic scintillator was used to acquire arterial input data. A nonlinear iterative least-squares fitting procedure that included terms for the vascular fraction and time delay to the peripheral sampling site was used to fit a three-compartment model to the brain data. Regions studied included frontal, temporal, occipital, and the entire cortex and subcortical white matter. The values obtained for the individual rate constants and regional CMRglc (rCMRglc; calculated using regional values of the rate constants) were higher than those reported previously. A significant (p less than 0.05) decrease was found in K1* in frontal and temporal cortex in the AD patients compared with the controls, with values of 0.157 and 0.161 ml/g/min in frontal and temporal cortex, respectively, of controls and 0.127 and 0.126 ml/g/min in frontal and temporal cortex of the AD patients. rCMRglc was also significantly (p less than 0.02) lower in the AD patients than controls in all cortical brain regions. Lower values of k3* were found in all brain regions in the AD patients, although these were not statistically significant. These findings provide evidence of an in vivo abnormality of forward glucose transport in AD.(ABSTRACT TRUNCATED AT 250 WORDS)

Forecasting coronary heart disease incidence, mortality, and cost: the Coronary Heart Disease Policy Model.

A computer simulation model was developed to project the future mortality, morbidity, and cost of coronary heart disease (CHD) in the United States population. The model contains a demographic-epidemiologic (DE) submodel, which stimulates the distribution of coronary risk factors and the conditional incidence of CHD in a demographically evolving population; a "bridge" submodel, which determines the outcome of the initial CHD event; and a disease history (DH) submodel, which simulates subsequent events in persons with a previous CHD event. The user of the model may simulate the effects of interventions, either preventive (i.e., risk factor modification) or therapeutic, upon mortality, morbidity, and cost for up to a 30-year period. If there were no future changes in risk factors or the efficacy of therapies after 1980, baseline projections indicate that the aging of the population, and especially the maturation of the post-World War II baby-boom generation, would increase CHD prevalence and annual incidence, mortality, and costs by about 40-50 per cent by the year 2010. Unprecedented reductions in risk factors would be required to offset these demographic effects on the absolute incidence of CHD. The specific forecasts could be inaccurate, however, as a consequence of erroneous assumptions or misestimated baseline data, and the model awaits validation based on actual future data.