Cost-effectiveness analysis of screening for asymptomatic, unruptured intracranial aneurysms. A mathematical model.
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BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) due to aneurysmal rupture is a major cause of cerebrovascular disease-related death. This problem could be eliminated by diagnosis and successful treatment of aneurysms before rupture. Recent developments in high-resolution imaging technology have made screening for unruptured aneurysms possible in the general population. Such screening has become widespread in Japan ("No Dokku, " or brain checkup). As a result, unruptured aneurysms are being identified with increasing frequency. However, the economic implications of treatment decisions for unruptured aneurysms have not been analyzed. Therefore, we performed such an analysis. METHODS: We used a Markov model to evaluate the cost-effectiveness of screening for asymptomatic, unruptured intracranial aneurysms. The model involved a set of variables describing discrete health states. Each state was assigned a quality of life score and an associated medical cost. A comparison of the expected outcomes was then made between 2 hypothetical cohorts, one receiving screening and the other no screening. A sensitivity analysis was performed by altering the input values within clinically reasonable ranges to reflect uncertainty in the baseline analysis and then assessing the effects on outcomes. RESULTS: Combining the incremental cost and effectiveness data revealed a cost per quality-adjusted life-year of $7760 for an annual rate of subarachnoid hemorrhage due to unruptured aneurysms (rupture rate) of 0.02; this cost was $39 450 for a rupture rate of 0.01. There was no benefit (negative quality-adjusted life-year benefit) for a rupture rate of 0.005, the rupture rate found in a recently published international cooperative study. The risks of surgery for unruptured aneurysms and the discounting ratio used to assess the impact of timing of costs and benefits on future outcomes also had significant effects on the results. Other variables had little impact on cost-effectiveness. CONCLUSIONS: The cost-effectiveness of screening for an unruptured aneurysm is highly sensitive to the annual rate of subarachnoid hemorrhage due to unruptured aneurysms. The low annual rupture rate seen in the recent large international cooperative study implies that screening asymptomatic populations to identify and treat unruptured aneurysms would not be cost cost-effective. (+info)
Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine-scale genetic mapping.
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Linkage disequilibrium (LD) is of great interest for gene mapping and the study of population history. We propose a multilocus model for LD, based on the decay of haplotype sharing (DHS). The DHS model is most appropriate when the LD in which one is interested is due to the introduction of a variant on an ancestral haplotype, with recombinations in succeeding generations resulting in preservation of only a small region of the ancestral haplotype around the variant. This is generally the scenario of interest for gene mapping by LD. The DHS parameter is a measure of LD that can be interpreted as the expected genetic distance to which the ancestral haplotype is preserved, or, equivalently, 1/(time in generations to the ancestral haplotype). The method allows for multiple origins of alleles and for mutations, and it takes into account missing observations and ambiguities in haplotype determination, via a hidden Markov model. Whereas most commonly used measures of LD apply to pairs of loci, the DHS measure is designed for application to the densely mapped haplotype data that are increasingly available. The DHS method explicitly models the dependence among multiple tightly linked loci on a chromosome. When the assumptions about population structure are sufficiently tractable, the estimate of LD is obtained by maximum likelihood. For more-complicated models of population history, we find means and covariances based on the model and solve a quasi-score estimating equation. Simulations show that this approach works extremely well both for estimation of LD and for fine mapping. We apply the DHS method to published data sets for cystic fibrosis and progressive myoclonus epilepsy. (+info)
Laparotomy versus no laparotomy in the management of early-stage, favorable-prognosis Hodgkin's disease: a decision analysis.
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PURPOSE: To perform a decision analysis that compared the life expectancy and quality-adjusted life expectancy of early-stage, favorable-prognosis Hodgkin's disease (HD) managed with and without staging laparotomy, incorporating data on treatment outcomes of HD in the modern era. METHODS: We constructed a decision-analytic model to compare laparotomy versus no laparotomy staging for a hypothetical cohort of 25-year-old patients with clinical stages I and II, favorable-prognosis HD. Markov models were used to simulate the lifetime clinical course of patients, whose prognosis depended on the true pathologic stage and initial treatment. The baseline probability estimates used in the model were derived from results of published studies. Quality-of-life adjustments for procedures and treatments, as well as the various long-term health states, were incorporated. RESULTS: The life expectancy was 36.67 years for the laparotomy strategy and 35.92 years for no laparotomy, yielding a net expected benefit of 0.75 years for laparotomy staging. The corresponding quality-adjusted life expectancies for the two strategies were 35.97 and 35.38 quality-adjusted life years (QALYs), respectively, resulting in a net expected benefit of laparotomy staging of 0.59 QALYs. Sensitivity analysis showed that the decision of laparotomy versus no laparotomy was most heavily influenced by the quality-of-life weight assigned to the postlaparotomy state. CONCLUSION: Our model predicted that on average, for a 25-year-old patient, proceeding with staging laparotomy resulted in a gain in life expectancy of 9 months, or 7 quality-adjusted months. These results suggest that a role remains for surgical staging in the management of early-stage HD. (+info)
Evolutionary demographic models for mortality plateaus.
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Plateaus in the age pattern of hazard functions at extreme ages have been discovered in large populations of medflies, Drosophila, nematodes, and people. Mueller and Rose [(1996) Proc. Natl. Acad. Sci. USA 93, 15249-15253] have proposed several age-structured demographic models to represent effects of mutation accumulation and antagonistic pleiotropy on randomly evolving schedules of demographic rates. They assert that "evolutionary theory [as embodied in their models] predicts late-life mortality plateaus." This paper defines a class of Markovian models that includes those of Mueller and Rose and obtains a characterization of the possible limiting states. For the basic model, the result implies that schedules with late-life mortality plateaus above a minimal threshold are not limiting states. The models fail, but not for reasons previously conjectured. Transient states, visited early by the process, do display mortality plateaus. Other models from this class may have a role to play in reconciling observed plateaus with evolutionary theory. (+info)
Heuristic approach to deriving models for gene finding.
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Computer methods of accurate gene finding in DNA sequences require models of protein coding and non-coding regions derived either from experimentally validated training sets or from large amounts of anonymous DNA sequence. Here we propose a new, heuristic method producing fairly accurate inhomogeneous Markov models of protein coding regions. The new method needs such a small amount of DNA sequence data that the model can be built 'on the fly' by a web server for any DNA sequence >400 nt. Tests on 10 complete bacterial genomes performed with the GeneMark.hmm program demonstrated the ability of the new models to detect 93.1% of annotated genes on average, while models built by traditional training predict an average of 93.9% of genes. Models built by the heuristic approach could be used to find genes in small fragments of anonymous prokaryotic genomes and in genomes of organelles, viruses, phages and plasmids, as well as in highly inhomogeneous genomes where adjustment of models to local DNA composition is needed. The heuristic method also gives an insight into the mechanism of codon usage pattern evolution. (+info)
Rate and directionality of mutations and effects of allele size constraints at anonymous, gene-associated, and disease-causing trinucleotide loci.
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We studied the patterns of within- and between-population variation at 29 trinucleotide loci in a random sample of 200 healthy individuals from four diverse populations: Germans, Nigerians, Chinese, and New Guinea highlanders. The loci were grouped as disease-causing (seven loci with CAG repeats), gene-associated (seven loci with CAG/CCG repeats and eight loci with AAT repeats), or anonymous (seven loci with AAT repeats). We used heterozygosity and variance of allele size (expressed in units of repeat counts) as measures of within-population variability and GST (based on heterozygosity as well as on allele size variance) as the measure of genetic differentiation between populations. Our observations are: (1) locus type is the major significant factor for differences in within-population genetic variability; (2) the disease-causing CAG repeats (in the nondisease range of repeat counts) have the highest within-population variation, followed by the AAT-repeat anonymous loci, the AAT-repeat gene-associated loci, and the CAG/CTG-repeat gene-associated loci; (3) an imbalance index beta, the ratio of the estimates of the product of effective population size and mutation rate based on allele size variance and heterozygosity, is the largest for disease-causing loci, followed by AAT- and CAG/CCG-repeat gene-associated loci and AAT-repeat anonymous loci; (4) mean allele size correlates positively with allele size variance for AAT- and CAG/CCG-repeat gene-associated loci and negatively for anonymous loci; and (5) GST is highest for the disease-causing loci. These observations are explained by specific differences of rates and patterns of mutations in these four groups of trinucleotide loci, taking into consideration the effects of the past demographic history of the modern human population. (+info)
Markov chain Monte Carlo analysis of human Y-chromosome microsatellites provides evidence of biased mutation.
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We describe a Markov Chain Monte Carlo analysis of five human Y- chromosome microsatellite polymorphisms based on samples from five diverse populations. Our analysis provides strong evidence for mutational bias favoring increase in length at all loci. Estimates of population coalescent times and population size from our two largest samples, one African and one European, suggest that the African population is older but smaller and that the English East Anglian population has undergone significant expansion, being larger but younger. We conclude that Markov Chain Monte Carlo analysis of microsatellite haplotypes can uncover information not apparent when the microsatellites are considered independently. Incorporation of population size as a variable should allow us to estimate the timing and magnitude of major historical population trends. (+info)
Do elderly women have more physical disability than men do?
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This study investigated whether the commonly observed higher prevalence of physical disability among women is due to higher incidence rates or to other factors such as selective mortality or poor recovery. Methods included observed measures of prevalent lower body physical disability and potential risk factors at baseline (1989-1991) and 4-year follow-up of 2,025 community-dwelling adults aged 55 years and older in Marin County, California. Incidence, recovery, and mortality rates were determined at the follow-up examination. Results indicated that women had higher age-specific and age-adjusted prevalence rates at both examinations (odds ratios = 1.66 and 1.60, p<0.001) but that incidence rates were not significantly different (odds ratio = 1.12, 95% confidence interval: 0.77, 1.64). In the classic formulation, prevalence = incidence x duration, the higher prevalence rates in women could not be due to a higher incidence rate, but could be explained by longer duration due to lower recovery and mortality rates in women. Incident physical disability was predicted by prevalent chronic illnesses, poor vision, obesity, physical inactivity, poor memory, fewer social activities, and higher depression scores, but not by sex. Prevention efforts should concentrate on reducing known risk factors in both men and women and on promoting higher recovery rates among women. (+info)