Expected distribution of normal and abnormal results in multitest surveys of healthy subjects.
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MOTIVATION: Clustering is a useful exploratory technique for the analysis of gene expression data. Many different heuristic clustering algorithms have been proposed in this context. Clustering algorithms based on probability models offer a principled alternative to heuristic algorithms. In particular, model-based clustering assumes that the data is generated by a finite mixture of underlying probability distributions such as multivariate normal distributions. The issues of selecting a 'good' clustering method and determining the 'correct' number of clusters are reduced to model selection problems in the probability framework. Gaussian mixture models have been shown to be a powerful tool for clustering in many applications. RESULTS: We benchmarked the performance of model-based clustering on several synthetic and real gene expression data sets for which external evaluation criteria were available. The model-based approach has superior performance on our synthetic data sets, consistently selecting the correct model and the number of clusters. On real expression data, the model-based approach produced clusters of quality comparable to a leading heuristic clustering algorithm, but with the key advantage of suggesting the number of clusters and an appropriate model. We also explored the validity of the Gaussian mixture assumption on different transformations of real data. We also assessed the degree to which these real gene expression data sets fit multivariate Gaussian distributions both before and after subjecting them to commonly used data transformations. Suitably chosen transformations seem to result in reasonable fits. AVAILABILITY: MCLUST is available at http://www.stat.washington.edu/fraley/mclust. The software for the diagonal model is under development. CONTACT: kayee@cs.washington.edu. SUPPLEMENTARY INFORMATION: http://www.cs.washington.edu/homes/kayee/model.
MOTIVATION: An important application of microarray experiments is to identify differentially expressed genes. Because microarray data are often not distributed according to a normal distribution nonparametric methods were suggested for their statistical analysis. Here, the Baumgartner-Weiss-Schindler test, a novel and powerful test based on ranks, is investigated and compared with the parametric t-test as well as with two other nonparametric tests (Wilcoxon rank sum test, Fisher-Pitman permutation test) recently recommended for the analysis of gene expression data. RESULTS: Simulation studies show that an exact permutation test based on the Baumgartner-Weiss-Schindler statistic B is preferable to the other three tests. It is less conservative than the Wilcoxon test and more powerful, in particular in case of asymmetric or heavily tailed distributions. When the underlying distribution is symmetric the differences in power between the tests are relatively small. Thus, the Baumgartner-Weiss-Schindler is recommended for the usual situation that the underlying distribution is a priori unknown. AVAILABILITY: SAS code available on request from the authors.
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Time to flowering is central in determining the adaptation and productivity of chickpea in short-season temperate environments. We studied the genetic control of this trait in three crosses, 272-2 x CDC Anna, 298T-9 x CDC Anna, and 298T-9 x CDC Frontier. From each cross, 180 F2 plants and parents were evaluated for time to flowering under greenhouse conditions. In summer 2004, multiple generations including P1, F1, P2, F2, and F2:3 (also called MG5) were evaluated for time to flowering under field conditions. The data on time to flowering in the F(2) populations were continuous in distribution but deviated from normal distribution. The F2:3 families derived from this showed a bimodal distribution for time to flowering, a typical case of major-gene inheritance model with duplicate recessive epistasis. A joint segregation analysis of MG5 also revealed that time to flowering in chickpea was controlled by two major genes along with other polygenes. Late flowering was dominant over early flowering for both major genes with digenic interaction between them, mainly an additive x additive type. This information can be used to formulate the most efficient breeding strategy for improvement of time to flowering in chickpea in short-season temperate environments.
PURPOSE: Relative regional cerebral blood flow (rCBF) at rest was measured in 44 volunteers using both dynamic susceptibility contrast (DSC) MRI and (99m)Tc-HMPAO SPECT on the same day. METHOD: In MRI, a Gd-DTPA-BMA contrast agent bolus (0.3 mmol/kg body wt) was monitored with a simultaneous dual FLASH pulse sequence (time resolution 1.5 s). MRI-based rCBF images were calculated by singular value decomposition-based deconvolution of the measured tissue concentration-time curve with an arterial input function from a small artery within the imaging slice. In the SPECT investigation, 900 MBq of (99m)Tc-HMPAO was injected intravenously. Relative rCBF in gray matter in the thalamus and in frontal white matter was determined. RESULTS: The ratio of relative rCBF in gray matter to relative rCBF in white matter was 2.21 +/- 0.57 using MRI and 2.24 +/- 0.54 using SPECT (mean +/- SD). CONCLUSION: Relative rCBF maps from DSC MRI and (99m)Tc-HMPAO SPECT showed good agreement, and the MRI-based rCBF ratio correlated with the corresponding SPECT-based ratio (r = 0.79, p < 0.0000006).
The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochloride (BP) in the normal, conscious rat. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive-microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either BP at three dosage levels (3.0, 6.0, 12.0 mg/kg) or vehicle (VH) at infusion rates matching those of the BP protocol (0.0408 ml/min). The predominant effects of BP (cumulative dose = 9.0 mg/kg i.v.) in the conscious rat were reduced coronary vascular resistance and heart rate. BP showed selectivity for the coronary circulation since systemic vascular resistance was not significantly reduced until a cumulative i.v. dosage of 21.0 mg/kg was administered. BP had few effects on other regions of the peripheral circulation. BP (21 mg/kg) reduced blood flow and increased vascular resistance in the arterial circulations of four of six skeletal muscles studied although opposite effects occurred in two of six muscles studied. BP had no significant effect on blood flow or vascular resistance in the other major arterial circulations. The results of this study show that BP is a selective coronary vasodilator that also reduces the primary indices of myocardial oxygen demand. These results suggest that the clinical therapeutic antianginal efficacy of BP occurs through a combined effect to increase myocardial oxygen supply and to reduce myocardial oxygen demand.
The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.
This paper develops a method for appraising health status in elderly people. A frailty index was defined as the proportion of accumulated deficits (symptoms, signs, functional impairments, and laboratory abnormalities). It serves as an individual state variable, reflecting severity of illness and proximity to death. In a representative database of elderly Canadians we found that deficits accumulated at 3% per year, and show a gamma distribution, typical for systems with redundant components that can be used in case of failure of a given subsystem. Of note, the slope of the index is insensitive to the individual nature of the deficits, and serves as an important prognostic factor for life expectancy. The formula for estimating an individual's life span given the frailty index value is presented. For different patterns of cognitive impairments the average within-group index value increases with the severity of the cognitive impairment, and the relative variability of the index is significantly reduced. Finally, the statistical distribution of the frailty index sharply differs between well groups (gamma distribution) and morbid groups (normal distribution). This pattern reflects an increase in uncompensated deficits in impaired organisms, which would lead to illness of various etiologies, and ultimately to increased mortality. The accumulation of deficits is as an example of a macroscopic variable, i.e., one that reflects general properties of aging at the level of the whole organism rather than any given functional deficiency. In consequence, we propose that it may be used as a proxy measure of aging.
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The content of type I and III collagen in normal human skin from subjects of different ages was studied by means of a new high performance liquid chromatography method and by SDS-polyacrylamide gel electrophoresis and scanning electron microscopy. The ratio of types I and III collagen in covered skin remained constant throughout childhood and young adult life and the proportion of type III was shown to be the same as previously reported. However, in the elderly, the proportion of type III collagen in the dermis increased to a variable degree. Scanning electron microscopic examination showed a decrease in the number of collagen fibre bundles with age. Average bundle width varied significantly with age. These results may reflect an impaired synthesis of type I collagen in aged skin.
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